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Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Chen Xue, Qinfan Yao, Xinyu Gu and 6 more

Signal Transduction and Targeted Therapy · 2023 · Review · CC BY

doi:10.1038/s41392-023-01468-7

Abstract

The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT–related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved signaling pathway that functions in several crucial physiological processes, including hematopoiesis, differentiation, metabolism, and immune modulation.– Structurally, the JAK-STAT pathway involves transmembrane receptors, receptor-associated cytosolic tyrosine kinases (i.e. JAKs), and signal transducers and activators of transcription (i.e., STATs). The JAK protein family contains four members: JAK1, JAK2, JAK3, and TYK2.– The STAT family consists of seven proteins: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6.– The JAK-STAT signaling pathway was first discovered in investigations of interferon-related transcriptional activation. Subsequently, a general outline of the components and pathogenesis of the JAK-STAT signaling pathway was gradually completed over a period of about 20 years.– More than 50 types of cytokines, including interferons (IFNs), interleukins (ILs), and growth factors, have been shown to play roles in JAK-STAT signaling to fulfill regulatory functions in cell differentiation, metabolism, survival, homeostasis, and immune response. Once receptors bind to an extracellular ligand, JAKs initiate tyrosine phosphorylation of the receptors and recruit corresponding STATs.– The phosphorylated STATs then dimerize and enter the nucleus to regulate specific gene transcription. This process enables the rapid transmission of external signals to the nucleus to regulate biological and pathological processes. Genome-wide association studies for disease exploration have identified more than 200 somatic mutations and single-nucleotide polymorphisms of JAK-STAT pathway genes that are functionally correlated with human diseases, including rheumatoid arthritis (RA), hematological malignancies, and atopic dermatitis (AD).– Abnormal activation of JAK-STAT signaling has been identified in diverse immune-mediated conditions and cancers, including melanomas, glioblastomas, and head, neck, lung, pancreatic, breast, rectal, and prostate cancers.– Based on the ‘double-edged sword’ function of the JAK-STAT pathway in disease pathogenesis, numerous agents targeting the JAK-STAT pathway have been developed and tested in preclinical and clinical trials.– As a result, first-generation JAK inhibitors, such as ruxolitinib, tofacitinib, and baricitinib, have been approved for clinical use.– Furthermore, a new generation of selective JAK inhibitors has emerged as a promising option for drug development and has shown success in preclinical trials. Despite this progress, some studies have reported adverse effects of JAK inhibitors, including infection, hematologic events, Wernicke encephalopathy, and even cancer, emphasizing the need for follow-up studies and in-depth investigations on drug thresholds, the mechanisms of adverse events, and drug resistance.–

In this review, we have expanded and updated the comprehensive research on the components, classical activation, and negative regulation of JAK-STAT signaling based on prior research. We have placed a specific emphasis on the immunomodulatory role of JAK-STAT signaling and the genetic associations between the JAK-STAT signaling pathway and certain diseases. We also discuss in detail the application of JAK inhibitors for the treatment of immune-related and malignant diseases and summarize their efficacy and safety in a series of clinical and preclinical trials.

JAK, STAT, and the JAK-STAT pathway

The JAK-STAT pathway is an evolutionarily conserved signaling pathway activated by cytokine stimulation that enables extracellular signals to be transmitted across the cell membrane to the nucleus, causing changes in DNA transcription., JAK-STAT signaling regulates a variety of cellular functions, including proliferation, migration, differentiation, and apoptosis., Importantly, JAK-STAT signaling also has an important regulatory role in immune function.–

The JAK family

The JAK family of non-receptor tyrosine kinases consists of four proteins: JAK1, JAK2, JAK3, and TYK2.,– Each kinase functions as an intracellular adaptor protein for cytokine signaling.– JAK3 is expressed at high levels predominantly in hematopoietic cells, whereas the other members are widely expressed in many tissues., The JAK proteins are composed of the FERM (the complex of four point one, ezrin, radixin, and moesin), Src homology domain (SH2), pseudokinase, and kinase domains.– The FERM domain has a clover structure composed of F1, F2, and F3 substructures. The FERM and SH2 domains are primarily responsible for JAK binding to receptors. The pseudokinase domain regulates the activity of the kinase domain, which is essential for the phosphorylation of receptor tyrosine which leads to further phosphorylation of downstream molecules. The four domains can be further divided into seven partitions referred to as JH1–7.,, JH1 and JH2 are located at the C-terminal end of the protein, and JH3–7 is located at the N-terminal end.– JH1 encodes a kinase that phosphorylates an important component of the kinase domain of the substrate.– The main function of JH2, also known as the pseudokinase domain without kinase activity, is to enhance the kinase function of JH1. JH3 and JH4 maintain the stability of the kinase structure.– JH5, JH6, and JH7 are responsible for the attachment of JAK to corresponding receptors. Cytokines such as interferons, interleukins, and growth factors and their receptors are the main activators of JAK. The receptor-ligand complex activates receptor-bound JAK, which catalyzes the phosphorylation of a receptor tyrosine. The four known members of the JAK family each interact with specific cytokine receptors and recruit corresponding STATs to exert diverse biological functions.– JAK1, JAK3, and TYK2 are responsible for immune system development and immune regulation, whereas JAK2 mainly participates in hematopoiesis.–

The STAT family

STAT proteins are signaling molecules downstream of JAK. The STAT family members are STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6.– STATs consist of an N-terminal domain and coil, a helix domain, a DNA-binding domain, a connection domain, an SH2 domain, and a transcription-activation domain.– The N-terminal domain and coil promote the formation of STAT dimers. The helix domain regulates the processes of nuclear import and export.– The DNA-binding domain enables STATs to bind DNA as transcription factors. The SH2 domain recognizes phosphorylated tyrosine on specific cytokine receptors. After the receptor tyrosine is phosphorylated, cytosolic STATs are recruited to the activated receptor, and a STAT tyrosine is phosphorylated, leading to the formation of STAT dimers.– STAT dimers then enter the nucleus as a component of transcription factor complexes to promote the transcription of specific target genes., STATs are then dephosphorylated in the nucleus and returned to the cytoplasm. Within the STAT family, STAT3 has been acknowledged to play a central role in signal transmission from the plasma membrane to the nucleus, making it a promising target for drug development.–

Negative regulation of JAK-STAT signaling

Many regulators inhibit the activation of the JAK-STAT signaling pathway. There are three main types of JAK-STAT regulators: suppressors of cytokine signaling (SOCSs), protein inhibitors of activated STATs (PIASs), and protein tyrosine phosphatases.– The SOCS family are the major signaling molecules that attenuate the JAK-STAT pathway and include CIS, SOCS1, SOCS2, SOCS3, SOCS4, SOCS5, SOCS6, and SOCS7.– Structurally, all the SOCSs contain an SH2 domain and a SOCS cassette. SOCSs can be induced by cytokines such as IL-2, IL-3, and IFN-γ. The entry of activated STATs into the nucleus enhances the transcription of SOCSs, which exert negative regulatory effects on JAK-STAT signaling by blocking STAT-receptor binding, inactivating JAKs via the N-terminal kinase inhibitory structure, or binding and ubiquitinating JAKs or STATs for proteasomal degradation., A negative feedback loop is driven by the positive effect of activated STATs on the transcription of SOCSs. The PIAS family includes PIAS1, PIAS3, PIASx, and PIASy.– PIASs can interact with STAT to prevent STAT dimerization or prevent STAT dimers from binding to DNA. As phosphatases, protein tyrosine phosphatases can interact with receptors to dephosphorylate JAK. Protein tyrosine phosphatases can also directly dephosphorylate STAT dimers to inhibit JAK-STAT signaling (Fig. 1).,

The JAK-STAT pathway, immunoregulation, and lineage plasticity

Cytokines are crucial for humoral and cellular immune responses.,, A wide range of cytokines associated with autoimmune diseases, including IFNs, ILs, and colony-stimulating factors, exert pleiotropic effects primarily through a combination of type I and type II cytokine receptors.– The interaction of type I and type II cytokine receptors can activate JAKs and subsequently recruit STATs to transduce signals from cytokines (Table 1).,, Numerous studies have shown that cytokine-induced activation of the JAK-STAT pathway plays instrumental roles in the differentiation and development of immune cells and the homeostasis of the immune system (Fig. 2).– Under stimulation by different cytokines, the JAK-STAT signaling pathway performs complex functions in immune regulatory events, these functions include not only cancer cell recognition, triggered mainly by IFNs and STAT1 and STAT2 signaling, but also immune escape triggered mainly by IL-6-STAT3 signaling. JAK-STAT signaling has been widely shown to drive antitumor immune surveillance in response to cytokines (like IL-2, IL-15, and IFNs) by inducing the activation, cytotoxicity, and function of natural killer (NK) cells.– On the other hand, the JAK-STAT pathway has been implicated in the pathogenesis of numerous autoimmune diseases such as RA, inflammatory bowel disease, and AD., For example, IL-6 induced the phosphorylation of STAT3 and upregulated the differentiation of Th17 cells, contributing to RA development. Ma, C. S. et al. also showed that STAT3 deficiency resulted in the production of incomplete T follicular helper cells and reduction of B-cell helper activity. In animal models of spondyloarthritis (SpA), TYK2 was shown to be an essential mediator of IL-22–induced STAT3 phosphorylation to enhance type 3 immunity and accelerate SpA progression. Furthermore, multiple genome-wide association analyzes have clearly demonstrated that polymorphisms and mutations in the JAK-STAT pathway are associated with autoimmune diseases and immune-mediated cancers (Fig. 3).,, Casaca, V. I. et al. reported that the rs324011 polymorphism in STAT6 resulted in early immune dysregulation with depressed Treg function and increased Th1 response at birth. Fabre, A. et al. reported links between STAT3 gain-of-function mutations and early-onset polyautoimmunity. Mutated STAT3 was also reported to participate in the pathogenesis of immune-mediated aplastic anemia by altering the T-cell phenotype and giving cytotoxic properties to CD8+ T cells. Additionally, JAK mutations were revealed to block IFN-γ signal transmission, contributing to immune evasion and insensitivity to anti-PD-1/PD-L1 immunotherapy. Recent clinical trials have shown that targeting JAKs and preventing their phosphorylation suppresses abnormal immune and inflammatory responses caused by cytokines, providing reasonable and solid evidence to support the use of JAK inhibitors as therapies to treat autoimmune diseases and cancers.

The effects of the JAK-STAT pathway on disease progression are complex. Cellular plasticity enables cells to adopt new phenotypes in response to environmental changes.– Cancer cells amplify this plasticity to cause tumor heterogeneity, metastasis, and therapy resistance.,, The histologic transformation of lung cancers harboring epidermal growth factor receptor (EGFR) mutations from adenocarcinoma to aggressive neuroendocrine cancer is a notable example of lineage plasticity in cancer., Numerous lines of evidence suggest that JAK-STAT signaling is tightly connected to lineage plasticity and resistance through stem cell self-renewal modulation and multilineage differentiation.– One of the most outstanding examples of this is the contribution of activated JAK-STAT signaling to the lineage transition of prostate cancer from adenocarcinoma to neuroendocrine cancer., In liver cancer, JAK-STAT3 is involved in the RAS-induced, malignancy-associated trans-differentiation of hepatocytes into intrahepatic cholangiocarcinoma cells. Moreover, activation of the IL-6-JAK-STAT pathway by WNT5A is known to facilitate epithelial-mesenchymal transition (EMT) in keloid scarring. A more comprehensive understanding of the effects of the JAK-STAT signaling pathway on lineage plasticity will provide a plausible molecular basis for the development of new therapies for malignant diseases.

The JAK-STAT pathway and diseases

There is emerging evidence that JAK-STAT activation can play dual roles in diseases. Hyperactivation of the JAK-STAT pathway has been implicated in the poor outcomes of many diseases including melanomas, glioblastomas, and head, neck, lung, pancreatic, breast, rectal, and prostate cancers.,, Conversely, favorable regulatory roles of the JAK-STAT pathway have been demonstrated in head and neck squamous cell carcinomas and prostate and colorectal cancers. In the next sections, we have highlighted the critical roles of the JAK-STAT pathway in some common diseases, including rheumatoid arthritis, myeloproliferative neoplasms, kidney diseases, and prostate, breast, and lung cancers.

Rheumatoid arthritis

RA is a chronic inflammatory joint disease marked by progressive synovitis, leading to irreversible cartilage and bone erosion, eventual joint destruction, and functional disability.– A central feature of RA pathogenesis is the production of inflammatory cytokines such as TNF, IL-1, and IL-6 by synovial cells.– Several studies have reported that multiple proinflammatory cytokines drive RA progression by activating JAK-STAT signaling (Fig. 4).– Fibroblasts, the key drivers of inflammation in the RA-afflicted synovium, were confirmed to produce IL-6 in the presence of STAT4 activation to trigger continuous joint destruction. Mori T. et al. pointed out that the IL-6–STAT3 cytokine loop is activated by inflammatory cytokines that are highly expressed in RA, causing chronic and persistent inflammation and joint destruction. Fibroblast-like synoviocytes from patients with active RA display elevated STAT1 expression and activity., Increased STAT3 activity in synovial CD4+ T cells in RA results in increased numbers of Th17 cells and reduced numbers of Treg cells and is closely related to the severity of synovitis. JAK3, STAT4, and STAT6 are also highly expressed in CD1a+ dendritic cells of patients with RA and may help to identify RA at the synovium level.– Mouse models of proteoglycan-induced arthritis revealed that IL-4 controls inflammatory responses in RA by inhibiting IL-12-STAT4 signaling. Additionally, a gene ontology and pathway analysis revealed increased expression of type I IFN-inducible genes in the peripheral blood of patients with RA. Higgs, B. W. et al. demonstrated that an overactive type I IFN pathway is involved in the disease activity of RA. Another study showed that miR-17 suppressed the secretion of proinflammatory cytokines such as IL-6 and IL-1β and bound to STAT3 and JAK1 to play an anti-inflammatory and anti-erosive role in RA development. Wang, J. et al. reported that long intergenic non-protein-encoding long-chain RNA p53-induced transcript (LncRNA LINC-PINT) suppressed TNF-α–induced synovial fibroblasts in RA by upregulating SOCS1 levels.

JAK inhibitors were recently introduced as a novel type of disease-modifying antirheumatic drugs (DMARDs), which reduce synovitis and systemic inflammation and improve function in RA (Table 2). The European Society of Rheumatology (EULAR) in 2019 equated the application of JAK inhibitors with that of biological DMARDs (bDMARDs) in circumstances where conventional synthetic DMARDs (csDMARDs) are ineffective.– A large observational study of the efficacy of commonly used second-line RA drugs confirmed that JAK inhibitors were more effective than methotrexate.– Chen, C. et al. recently proposed that the JAK3 inhibitor Z583 irreversibly combines with cysteine residue 909 (Cys909) of JAK3 to prevent activation of JAK-STAT signaling, exerting powerful suppressive effects on RA progression. Given the expression and influence of JAK-STAT signaling in RA, JAK inhibitors are regarded as appropriate agents for RA management, although further large-scale studies are required to define more specific clinical applications of agents targeting JAK-STAT signaling in RA.–

Myeloproliferative neoplasms

Within hematology, JAK-STAT signaling has been explored in the context of myeloproliferative neoplasms (MPNs).– MPNs are clonal hematopoietic conditions characterized by excessive proliferation of myeloid lineage cells, which contributes to abnormal numbers and morphology of peripheral blood cells and a high-risk of acute myeloid leukemia development.– High-resolution genome-wide genotyping has identified acquired somatic mutations that are associated with increased JAK-STAT activity in various types of MPNs.– Numerous studies reported that JAK2 mutations are frequent in MPNs and exert disruptive effects on the regulation of diverse biological processes.– Rampal R et al. employed an integrated genomic analysis and found that the distinctive upregulation of JAK-STAT target genes helped distinguish different subtypes of MPNs, and the degree of valine-to-phenylalanine substitution at amino acid position 617 of JAK2 (JAK2V617F) influenced the disease severity. JAK2V617F results in constitutive tyrosine phosphorylation activity and is the most prevalent gain-of-function alteration in the majority of MPNs.,– Experiments with Pf4-Cre transgenic mice indicated that activated JAK-STAT signaling in megakaryocytes with the JAK2V617F mutation promoted the induction and maintenance of myeloproliferation in MPN through the production of proinflammatory cytokines and chemokines. Based on the association between JAK2V617F and MPN, the World Health Organization Classification and the International Consensus Classification both proposed a novel definition of “JAK2 mutation-prevalent MPNs”, which mainly consist of polycythemia vera, essential thrombocythemia, primary myelofibrosis, and unclassifiable MPN., Genomic analysis revealed frequent JAK2V617F mutations in over 90% of polycythemia vera cases and about 50% of essential thrombocythemia and primary myelofibrosis cases.

Calreticulin (CALR), a chaperone protein that localizes in the endoplasmic reticulum and participates in protein folding, is the second most frequently mutated protein in MPNs after JAK2. It is well established that CALR mutation is mutually exclusive with other MPN driver mutations, including JAK2V617F and the thrombopoietin receptor (MPL) mutation MPLW515L.– Whole-exome sequencing identified CALR mutations in ~70% to 80% of JAK2V617F-negative ETs and primary myelofibrosis., In vivo research demonstrated that CALR mutation alone was strong enough to initiate an MPN phenotype and increased JAK-STAT signaling activity. The cellular model revealed that CALR mutants specifically activated MPL to drive the pathogenesis of MPN. Elf, S. et al. further demonstrated that the malignant transformation driven by mutant CALR in MPN required interaction with MPL.,

Thrombopoietin and its receptor MPL are primary regulators of megakaryocyte growth and differentiation.– The pathogenetic mutation MPLW515L induces abnormal activation of JAK-STAT signaling and participates in MPN development., MPLW515L promotes hematopoietic cell proliferation and cellular responses to thrombopoietin. Lnk, the negative regulator of thrombopoietin, can reverse the growth-stimulating signals in cells carrying MPLW515L and cause malignant cells to die. Moreover, a study of a cohort of 1182 patients with MPN and the exploration of bone marrow-derived DNA from different disease courses consistently showed that MPLW515L and JAK2V617F occurred concurrently in MPNs, suggesting that the functions of these driver mutations may be relatively complementary in the course of MPN pathogenesis.,

Atopic dermatitis

Atopic dermatitis (AD) is one of the most common chronic immune-mediated skin conditions. Patients with AD suffer recurrent symptoms and impaired quality of life.– Existing therapies for AD relieve the symptoms but cannot delay disease progression, and all of these therapies have limitations in clinical applications., The pathogenesis of AD has a multifactorial origin and is considered to predominantly result from T helper 2 (Th2) cell-mediated inflammation and the gradual upregulation of Th1, Th17, and Th22 cell-mediated inflammation at the later stages of disease progression. A variety of mediators, including IL-4, IL-13, IL-31, and TSLP, bind specific transmembrane receptors and stimulate the JAK-STAT pathway, thereby initiating intracellular signaling and exerting proinflammatory effects in AD., In-depth explorations of AD pathogenesis have suggested that the JAK-STAT pathway is involved in Th2 immune polarization, eosinophil activation, and skin barrier destruction during AD progression.

A greater understanding of the roles of the JAK-STAT pathway in AD has enabled the application of JAK inhibitors as a new approach to AD treatment.– Baricitinib, an oral selective inhibitor of JAK1 and JAK2, has been approved for the treatment of moderate-to-severe AD. The results of two phase 3 trials (BREEZE-AD1 and BREEZE-AD2) have shown that baricitinib significantly relieves unbearable pruritus and skin lesions in patients with moderate-to-severe AD. Topical ruxolitinib has also shown anti-inflammatory and antipruritic effects in experimental models and phase 3 clinical trials (TRuE-AD1 and TRuE-AD2).– Given the close connection between JAK1 and the pathogenesis of AD, selective JAK1 inhibitors are promising therapeutic candidates for AD. Upadacitinib, was a highly specific JAK1 inhibitor previously explored in RA and further approved by the FDA in 2019 for the treatment of moderate-to-severe refractory AD in patients aged ≥12 years.– Mechanistically, upadacitinib relieves chronic dermatitis by potently attenuating the cytokines related to JAK1 inflammatory signaling (including IL-6 and IFNs).– The minimal effects of upadacitinib on JAK2 and JAK3 result in a few side effects, especially in the hemopoietic system.– Several phase 3 trials (Measure Up 1, Measure Up 2, and AD Up) have shown that upadacitinib as a monotherapy or in combination with topical corticosteroids has favorable efficacy and tolerability in patients with moderate-to-severe AD., In 2022, abrocitinib, a selective JAK1 inhibitor, was also approved for the treatment of moderate-to-severe AD.– Phase 3 studies including JADE MONO-1, MONO-2, and TEEN have shown that 200 or 100 mg abrocitinib was more effective than placebo or dupilumab in terms of the early alleviation of itch and reduction of the eczema area as well as the severity index (EASI-75) and Investigator’s Global Assessment (IGA) scores.– A phase 2 study (NCT02201524) also suggested that abrocitinib resulted in favorable symptom improvement in patients with moderate-to-severe psoriasis.

Hepatocellular carcinoma

Several studies have indicated that the JAK-STAT signaling pathway is widely involved in multiple types of solid cancers. Hepatocellular carcinoma (HCC) is a lethal and heterogeneous tumor with consistently high incidence and mortality rates, contributing to more than 700,000 deaths annually.– Chronic hepatitis B virus (HBV) infection occurs in more than 400 million people across the globe and is the most frequent cause of HCC. Despite improvements in the management of HCC, the clinical prognosis of HCC remains unfavorable, with a 5-year survival rate of 10%. The process of hepatic carcinogenesis is thought to involve a series of genetic alterations and abnormal changes in signaling pathways.– The JAK-STAT signaling pathway has been extensively explored for potential roles in HCC pathogenetic progress. The use of interferon-alfa (IFN-α) to drive host antiviral responses is the current first-line treatment for chronic hepatitis B and has been verified to slow the progression of liver fibrosis and even the occurrence of HCC. As a crucial immune-related cytokine, IFN-α activates JAK-STAT signaling to induce various IFN-stimulated genes with antiviral and immunomodulatory functions. Han M et al. found that the expression and activation of IFN-stimulated genes including STAT1, myxovirus resistance (Mx), and SOCS3 in the peripheral blood of patients with chronic hepatitis B were closely correlated with IFN-induced antiviral outcomes., SOCS3 overexpression following HBV infection caused the inactivation of IFN signaling and was correlated with the severity of liver inflammation., In an HBV-producing HepG2 cell line, Hepatitis B Virus X protein weakened IFN-α signaling by inactivating STAT3 to increase SOCS3 and protein phosphatase 2 A expression. Gao D et al. also observed downregulation of SOCS3 by miR-122 increased the anti-HBV effectiveness of IFN. Numerous studies reported that SOCS3 is downregulated in HCC tissues and is negatively implicated in HCC malignant transformation., SOCS3 methylation was discovered to be more frequent in HBV-positive HCC than in normal liver tissues and was associated with poor HCC outcomes. Eyes absent homolog 2, which transcriptionally upregulates SOCS3 expression to block JAK-STAT signaling, was identified as a potential tumor suppressor in HCC and found to inhibit HCC progression. Conversely, CircSOD2 suppressed SOCS3 expression and triggered JAK2–STAT3 signaling to drive HCC progression. Furthermore, as a member of the B7 family of immune checkpoint proteins, HHLA2 was demonstrated to activate the JAK-STAT pathway and accelerate HCC progression by binding to TMIGD2.

Prostate cancer

Androgen receptor (AR)-targeted therapies such as enzalutamide have achieved considerable clinical success in patients with prostate cancer, mainly by attacking the glandular luminal cells. Unfortunately, advanced prostate cancer usually undergoes lineage conversion into squamous cell carcinoma or neuroendocrine cancer, resulting in drug resistance. Several studies have found associations between excessive JAK-STAT signaling activation in prostate cancer and the regulation of lineage plasticity, resistance to AR-targeted therapies, and poor clinical outcomes., JAK1, JAK2, STAT1, and STAT3 are essential drivers of lineage plasticity in cancer cells. In particular, constitutively activated STAT3 promotes lineage plasticity and associated cell migration and invasion., In mouse organoids, genetically engineered mouse models (GEMMs), and human cell lines, combined with fibroblast growth factor receptor (FGFR) signaling, the JAK-STAT pathway was shown to trigger luminal-basal phenotype conversion and subsequent castration-resistant prostate cancer (CRPC) formation. The pharmacological inhibition of JAK-STAT signaling in vitro and in vivo led to the re-sensitization of resistant cancer cells to enzalutamide and effectively reversed the undesirable phenotypic plasticity. These results provide vital theoretical support for new approaches to overcome drug resistance in CRPC and shed light on the association between lineage plasticity and carcinogenesis.

Breast cancer

Breast cancer is the most prevalent cancer in women worldwide. There are three general categories of breast cancer: hormone receptor-positive (HR+), human epidermal growth factor receptor-positive (HER2+), and triple-negative (TN).– Distant metastasis and therapy resistance are the root cause of the poor prognosis of the majority of patients with breast cancer., Accumulating evidence suggests that all the STAT family members are closely associated with breast cancer, having either pro-tumorigenic or antitumorigenic characteristics. Therefore, breast cancer provides an example of the double-edged sword role of JAK-STAT in carcinogenesis.

As an essential regulator of cell transformation and apoptosis during breast development, STAT3 has been extensively explored in the context of breast cancer., Several studies have shown that STAT3 plays a central role in the proliferation, invasion, metastasis, and immune escape of breast cancer cells., Moreover, STAT3 helps maintain the phenotype and function of breast cancer stem cells (BCSCs), which display pluripotent properties, resistance to chemotherapy, and high capacity for self-renewal.– The classical IL-6-JAK-STAT3 pathway upregulates genes related to breast cancer progression, induces resistance to aromatase inhibitor (AI) chemotherapy, and correlates with poor survival in HR+ breast cancer.– In patients with HER2+ breast cancer, alone or in combination with trastuzumab, the selective JAK1/2 inhibitor ruxolitinib weakens cancer cell viability and improves the clinical outcomes by inhibiting the IL-6–JAK2–STAT3–calprotectin axis.

Despite the pro-tumorigenic effects of JAK-STAT signaling, some preclinical studies have shown that JAK inhibitors impair the antitumor immunity of NK cells and increase the metastatic burden in breast cancer. Furthermore, ruxolitinib, a JAK1 and JAK2 inhibitor, can induce the generation of proinflammatory mediators by macrophages, resulting in the establishment of a pro-tumorigenic microenvironment and drug resistance in breast cancer. The diverse effects of the JAK-STAT pathway in breast cancer highlight the importance of JAK-STAT signaling and offer insights into the development of effective therapeutic strategies.

Kidney diseases

With the notable exceptions of RA, hematological malignancies, and solid cancers, it’s also reported by the transcriptome analysis that increased STAT1 and STAT3 expression in kidney glomerular and tubulointerstitial sections were associated with disease progression in focal segmental glomerulosclerosis. Pang et al. confirmed that STAT3 activation mediated renal fibrosis in unilateral ureteral obstruction models, and the application of the novel STAT3 inhibitor S3I-201 suppressed renal interstitial fibroblast activation and fibrosis. By contrast, Koike, K. et al. observed that activated JAK-STAT3 signaling in unilateral ureteral obstruction models induced matrix metalloproteinase-2 expression in proximal tubular cells to relieve renal fibrosis and promote tissue repair. The conflicting findings regarding the functions of JAK-STAT signaling in renal tissue repair and fibrosis may result from differences in animal models and the interventions applied to regulate the JAK-STAT pathway.

STAT3 activation induced by hyperuricemia in tubular and interstitial cells was accompanied by kidney fibrosis and dysfunction, and the STAT3 inhibitor S3I-201 was confirmed to suppress the JAK-STAT pathway to achieve anti-fibrotic effects. In an exploration of kidney tubulointerstitial fibrosis, miR-150–based RNA interference was confirmed to reverse activation of the SOCS1-JAK-STAT pathway and alleviate tubulointerstitial fibrosis. In addition, overactive STAT1 and STAT3 expression and activated JAK-STAT signaling were demonstrated to accompany progressive kidney inflammation and proteinuria in IgA nephropathy.

Activation of JAK-STAT signaling was also found to play an essential pathogenic role in renal damage caused by diabetes mellitus through the stimulation of excessive glomerular mesangial cell growth.– Increased activity of the JAK-STAT pathway in mice with diabetic nephropathy prevented podocyte autophagy and enhanced disease progression. A remarkable increase in JAK2 level was also integrally linked to a series of deteriorating clinical symptoms of diabetic nephropathy, including albuminuria, glomerulosclerosis, and reduced numbers of podocytes. In STZ-induced diabetic rat models, hyperglycemia triggered the JAK-STAT pathway in glomerular mesangial cells through angiotensin II, and treatment with angiotensin II blockade reversed pathological changes to improve kidney function.

Autosomal dominant polycystic kidney disease (ADPKD), the most common congenital kidney disorder, is commonly accompanied by abnormal activity of JAK-STAT pathways., Forced STAT5 expression in ADPKD causes aberrant proliferation by transcriptionally upregulating cyclin D1 in a growth hormone-dependent manner. Pkd1nl/nl murine models revealed heterotopic JAK2 expression in cyst-lining cells and interstitium and validated that JAK2 inhibition could postpone cystic growth in ADPKD.

Experiments using an MRL/lpr mouse model indicated that renal CD8+ tissue-resident memory T cells required JAK/STAT signaling for self-renewal and effector functions, which were related to lupus nephritis activity. The STAT3 level was also dramatically elevated in lupus nephritis and linked to unfavorable clinical parameters. In non-human primate allograft models based on calcineurin-inhibitor-free regimens, use of the JAK3 inhibitor CP-690,550 in combination with mycophenolate mofetil lowered the incidence of kidney acute rejection and prolonged allograft survival.– Additionally, JAK-STAT signaling triggered by IFN-γ was demonstrated to be inhibited by the FGFR pathway in renal cell carcinoma cells, and treatment with lenvatinib, a targeted FGFR receptor tyrosine kinase inhibitor, recovered antitumor immunity and enhanced the efficacy of immune checkpoint inhibitors.

JAK-STAT pathway and treatment

The JAK-STAT signaling pathway is the essential intracellular route through which diverse extracellular soluble molecules bind membrane receptors and transfer signals to the nucleus. Given its primary roles in a series of cancers and autoimmune diseases, JAK-STAT signaling has emerged as a prominent target for drug development. Drugs that target the JAK-STAT pathway can be classified into three groups according to how they affect the signal transduction process: cytokine or receptor antibodies, STAT inhibitors, and JAK inhibitors.–

Upstream cytokines and receptors are pivotal for modulating the functions of the JAK-STAT signaling pathway.– Drugs that manipulate JAK-STAT-dependent cytokines and receptors (e.g., siltuximab and tocilizumab for the classical blockade of IL-6) inhibit JAK-STAT signal transduction and have therefore been used as therapeutic interventions in many diseases.–

Most STAT inhibitors function by restricting STAT phosphorylation, inhibiting SH2-mediated dimerization, or inducing STAT degradation.– Given the crucial functions of activated STAT3 and STAT5 in signal transduction and pathogenic progression, multiple inhibitors targeting STAT3 and STAT5, including peptides, peptidomimetics, oligonucleotides, siRNAs, small molecules, and metal-based complexes, have shown promising preclinical efficacy.– Hundreds of research articles have described the various underlying mechanisms of STATs in disease progression and the efficacies of dozens of STAT inhibitors in preclinical and clinical trials.

STAT3, the most widely studied STAT protein, is frequently mutated and overactivated in diverse cancers and promotes cancer cell proliferation, invasion, metastasis, and immune evasion. Napabucasin (BBI608), the first direct STAT3 inhibitor to enter phase 3 clinical trials and the first-in-class cancer stemness inhibitor, has been shown to restrain diverse malignant processes in multiple cancers. Moreover, napabucasin was found to decrease the expression of critical stemness-related genes, deplete cancer stem cell (CSC) populations and re-sensitize chemo-resistant cells to cisplatin in cisplatin-resistant NSCLC models. Napabucasin also possesses anti-acute myeloid leukemia (AML) properties and enhanced the Bcl-2 inhibitor efficacy by inhibiting STAT3 and inducing DNA damage, as revealed in in vitro and in vivo experiments. In addition, napabucasin eliminated the immunosuppressive functions of both murine and human myeloid-derived suppressor cells (MDSCs) in malignant melanoma and was found to be associated with the patients’ clinical outcomes. A recent phase 3 trial (NCT01830621) of napabucasin monotherapy in advanced colorectal cancer showed that its potential outcomes in terms of patient prognosis were better in the napabucasin group than in the placebo group. Moreover, napabucasin has been recently approved by the FDA as an orphan drug for gastric and pancreatic cancer treatment. And OPB-31121, a novel STAT3 inhibitor, induces cell apoptosis and was shown to exert synergism with 5-fluorouracil and cisplatin in both gastric cancer cells and xenograft models. Additionally, OPB-51602, a selective inhibitor of STAT3 phosphorylation, reduces complex I activity and increases ROS concentrations to maintain high toxicity to cancer cells. OPB-51602 was observed to improve acquired drug resistance by preventing the reliance of cancer cells on mitochondrial oxidative phosphorylation (OXPHOS)., In a first-in-human phase I clinical trial (NCT01184807), OPB-51602 exhibited promising antitumor activity among patients with refractory solid tumors, especially NSCLC. Moreover, TTI-101 (C188-9), another STAT3 inhibitor, was found to attenuate the activation of the phosphotyrosine (pY) peptide-binding site within the SH2 domain of STAT3, without the influence of mitochondrial function. Multiple studies conducted in animal models have demonstrated effective therapeutic potential and favorable safety profiles in a series of autoimmune diseases and cancers, including SSc, Crohn’s disease, head and neck cancer, and lung, breast, colorectal, and liver cancers.– Most recently, TTI-101 has been granted the ‘fast track’ designation by the FDA for applying relapsed/refractory locally advanced, unresectable, or metastatic hepatocellular carcinoma. An ongoing phase 1 clinical trial of TTI-101 (NCT03195699) has reported that patients with advanced solid tumors tolerated the administration of TTI-101 well.

Moreover, emerging studies have revealed the potential of STAT5 inhibitors. A prior study has demonstrated that STAT5 programs the new generation of GM-CSF-producing T helper (TH) cells (TH-GM), which cause more severe neuroinflammation than TH1 and TH17 cells. The preliminary result of a STAT5 inhibitor clinflamozyde in a recent COVID-19 clinical trial approved by the FDA observed that clinflamozyde selectively repressed the STAT5-TH-GM pathway to relieve severe cytokine storms and significantly improved clinical outcomes of patients with COVID-19.

Moreover, increasing strategies integrating STAT3 with immune checkpoint inhibitors (e.g., anti-CTLA-4 and PD-1/PD-L1 antibodies), CAR-T-cell therapy (NCT02906371), stimulator of interferon genes (STING) agonists, and even cancer vaccines have shown encouraging synergistic antitumor efficacy in diverse preclinical trails.,–

Based on the previous exploration, STAT inhibitors have demonstrated promising value in their antitumor effects. Unfortunately, most STAT inhibitors are still in the preclinical stages of development, and few have been approved for clinical application owing to the lack of intrinsic catalytic activity and selectivity shown by most candidates. A large number of clinical trials targeting STATs as monotherapies and combination therapies are currently underway, offering an attractive drug target for disease treatment.

Despite this, natural products and their derivatives have served as sources of novel antitumor agents based on the JAK-STAT pathway.– Over the past several decades, in vitro and in vivo experiments have shown that various natural products have inhibitory effects on the STAT3 signaling pathway and exhibit promising anticancer activities. For example, the phytochemical curcumin was shown to effectively inhibit STAT3 and play anticancer roles in breast, ovarian, lung cancer, and esophageal squamous cell carcinoma.– Moreover, the natural flavonoid myricetin was found to downregulate the levels of programmed death ligand-1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO1) and restore T-cell activity and antitumor immunity by inhibiting the IFN-γ-activated JAK-STAT–IRF1 axis in lung A549, breast MDA-MB-231 and colon HCT116 cancer cells., Runtsch et al. proposed that the natural metabolite itaconate and its derivatives inhibit M2 polarization by blocking JAK1-STAT6 pathway phosphorylation, providing a novel perspective on M2 macrophage-driven diseases. As a new natural STAT3 inhibitor, XYA-2 was found to bind the SH2 domain of STAT3 and synergistically downregulate the levels of MYC and SLC39A10 in human gastric cancer cell lines and patient-derived xenograft (PDX) mouse models to perform its anticancer roles.

In addition, SOCS proteins, as part of a negative feedback loop in the JAK-STAT pathway, and peptides targeting SOCS interactors have also shown promise as inhibitors of disease progression.,,

Recently, several JAK inhibitors have been clinically approved for the treatment of various diseases, and a growing body of innovative drug candidates are in preclinical and clinical trials (Table 3). Here, we review the critical applications and adverse events of the major JAK inhibitors in human diseases.

JAK inhibitors are small-molecule inhibitors that cause immunosuppression, reduce the pathological production of proinflammatory cytokines driven by JAK-STAT signaling, and inhibit gain-of-function JAK mutants., Various JAK inhibitors are currently in preclinical and clinical studies to treat a series of autoimmune diseases and cancers.–

The first-generation oral JAK inhibitors revolutionized the treatment of a group of heterogeneous disorders. The first clinically approved JAK inhibitor was the JAK1 and JAK2 inhibitor ruxolitinib, which was approved by the U.S. Food and Drug Administration (FDA) in 2011 to treat myelofibrosis.,– The COMFORT-I trial conducted by Verstovsek, S. et al. demonstrated the clinical benefits of ruxolitinib for patients with intermediate-2 or high-risk myelofibrosis; the ruxolitinib group showed improved manifestations, reduced spleen size, and elevated overall survival compared with the placebo group. Later, the COMFORT-II trial showed that patients with myelofibrosis benefited from continuous ruxolitinib therapy in comparison with patients that received the best available therapy, highlighting the long-term effectiveness and overall survival benefits of ruxolitinib. Kvasnicka, H. M. et al. reported that long-term administration of ruxolitinib for 48 months or 60 months ameliorated and stabilized the progression of bone marrow fibrosis. Zeiser et al. conducted a phase 3 trial to assess the efficacy of ruxolitinib in patients with glucocorticoid-refractory or -dependent chronic graft-versus-host disease. The results showed that 165 patients that received ruxolitinib manifested more favorable overall responses at 24 weeks, a longer duration of response at 12 months, and better failure-free survival than patients that received common second-line therapies. In a single-center retrospective study of patients with inflammatory bowel disease, 6 months of ruxolitinib treatment resulted in improved extraintestinal symptoms, stool frequency, steroid taper, and nutritional status. A case report suggested that the use of ruxolitinib early in the disease courses of refractory systemic idiopathic juvenile arthritis and interstitial lung diseases may block IFN-γ signaling to postpone disease-related deterioration. More recently, the RUXCOVID phase 3 trial randomly divided 432 patients into a ruxolitinib group (n = 287) and a placebo group (n = 145) plus standard of care to estimate the efficacy of ruxolitinib for the treatment of coronavirus disease 2019 (COVID-19). The results indicated that the median recovery time was 1 day less for patients treated with ruxolitinib compared with patients that received placebo. However, Fisher, D. et al. recently pointed out that multi-cytokine overproduction persisted in patients with myelofibrosis after treatment with ruxolitinib. Notably, a 75-year-old man with myelofibrosis was reported to develop progressive multifocal leukoencephalopathy after receiving ruxolitinib treatment. Several studies have also reported that the rapid discontinuation of ruxolitinib administration induced life-threatening withdrawal symptoms, which may be attributed to robust changes in the activities of inflammatory cytokines.–

The preferentially selective JAK3 and JAK1 inhibitor tofacitinib was the first JAK inhibitor approved for patients with RA that had poor responses to conventional drugs like methotrexate., Several studies showed that tofacitinib was consistently more efficacious and safer compared with other DMARDs in patients with RA.– In recent years, tofacitinib exhibited promising efficacy in clinical trials for diverse autoimmune diseases.,– Tofacitinib was approved by the FDA for the treatment of active ulcerative colitis in 2018 and was also later validated in numerous studies to be safe and effective for the treatment of inflammatory bowel diseases.– Sandborn, W. J. et al. performed three phase 3 trials and confirmed the favorable efficacy of tofacitinib as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Then, they further integrated several global clinical trials and validated the long-term safety and effectiveness of tofacitinib for patients with ulcerative colitis. In an open-label trial involving 10 patients with sarcoidosis, tofacitinib ameliorated skin and internal-organ symptoms in all 10 patients chiefly by suppressing type 1 immunity. You, H. et al. indicated that tofacitinib was the same or better than conventional immunosuppressants for improving the modified Rodnan skin score of patients with refractory skin thickening in diffuse cutaneous systemic sclerosis. Changelian, P. S. et al. demonstrated the potential benefit of tofacitinib for preventing allograft rejection in vivo by showing that tofacitinib mediated immunosuppression to prevent organ rejection in a murine model of heart transplantation and in a non-human primate model of kidney transplantation. To further explore the safety of tofacitinib in a real-world setting, Khosrow-Khavar, F. et al. enrolled two cohorts of patients with RA that received either tofacitinib or tumor necrosis factor (TNF) inhibitor and found a statistically insignificant increase in adverse cardiovascular outcomes in patients after tofacitinib treatment. However, the ORAL Surveillance reported that tofacitinib caused higher rates of infection and cardiovascular events compared with tumor necrosis factor inhibitors in patients with RA that were more than 50 years of age and had at least one additional cardiovascular risk factor. In preclinical trials and preclinical genetic studies, ruxolitinib was found to exhibit potential cardiotoxicity that may present as toxic myocardial damage, decreased left ventricular systolic function, or cardiac failure.–

The selective JAK1 and JAK2 inhibitor baricitinib was approved for the treatment of RA in 2017 and has been widely confirmed to improve clinical symptoms of RA in patients that have an inadequate response to methotrexate., The RA-BEAM trial involving patients with moderately to severely active RA and an inadequate response to methotrexate showed that baricitinib was superior to placebo with respect to signs and symptoms, physical function, and joint structural damage.– Baricitinib also produced better improvements than adalimumab according to the criteria of the American College of Rheumatology (ACR20 response) and Disease Activity Score 28-joint count C reactive protein (DAS28-CRP).– The RA-BEACON trials explored the efficacy of baricitinib in patients with RA that were refractory to bDMARDs. In two phase 3 trials in patients with severe alopecia areata, baricitinib was superior to placebo in producing hair regrowth.. Baricitinib was also found to have a high affinity for numb-associated kinase (NAK) which enabled it to suppress NAK activity and block clathrin-mediated endocytosis to reduce viral infection in COVID-19., In addition, a pilot study showed that baricitinib improved respiratory symptoms and did not cause serious adverse events in 12 patients with mild-to moderate COVID-19 pneumonia. Cantini, F. et al. also performed a retrospective multicenter study of 113 consecutive patients hospitalized with moderate pneumonia and validated the beneficial effects of baricitinib in terms of reduced viral burden, mortality, and hospitalization rates. The ongoing RECOVERY trial further confirmed the effectiveness of baricitinib in reducing mortality due to COVID-19. An integrated study of 3,492 patients with RA that received baricitinib found no correlation between baricitinib use and major adverse cardiovascular events, arterial thrombotic events, or congestive heart failure.

Peficitinib, a pan-JAK inhibitor that significantly inhibits JAK3, was approved for the treatment of RA in Japan in 2019. Numerous phase 2b (e.g., RAJ1, RA21, and RA22) trials have shown that peficitinib, as a monotherapy or combined with csDMARDs, achieved a rapid and statistically significant American College of Rheumatology (ACR) response rate over 12 weeks in patients with moderate-to-severe RA.,, The phase 3 trial (RAJ3 and RAJ4) also observed that peficitinib performs better in alleviating RA symptoms and joint destruction after 12 weeks of treatment. In addition, a phase 2b trial showed that patients with ulcerative colitis receiving ≥75 mg of peficitinib exhibited higher rates of clinical response, remission, and mucosal healing at week 8. Based on the outcomes of a phase 2a multicenter placebo-controlled study, peficitinib also exhibited dose-dependent improvements in clinical and histological lesions among patients with moderate-to-severe psoriasis. Furthermore, the safety profile of peficitinib is acceptable, commonly including nasopharyngitis, herpes zoster, diarrhea, increased blood creatine phosphokinase levels, and lymphopenia. Delgocitinib, a pan-JAK inhibitor with broad inhibitory effects on proinflammatory cytokines, is effective against diverse inflammatory skin conditions, including AD, eczema, discoid lupus erythematosus, psoriasis, and alopecia areata.– In phase 3 trials, the topical administration of delgocitinib produced clinically meaningful improvements in efficacy endpoints for patients with moderate-to-severe AD, resulting in the approval of delgocitinib for AD treatment. Moreover, throughout the study periods in both children and adults with AD, the majority of adverse events were mild and not relevant to the use of delgocitinib.–

The first-generation JAK inhibitors are considered to be pan-JAK inhibitors that target multiple JAK isoforms. Given their highly conserved ATP-binding sites, JAK inhibitors produce a wide range of effects but also cause side effects including cardiovascular events, thromboembolic events, infection, and oncogenic complications. Therefore, the development of more selective JAK inhibitors with an emphasis on enhanced specificity and fewer adverse effects has become a focus of drug research. Fedratinib is a selective JAK2 inhibitor that was approved by the FDA in 2019 to treat patients with intermediate-2 or high-risk myelofibrosis.– The National Comprehensive Care Network also classified fedratinib as a category 1 recommendation for higher-risk patients with myelofibrosis and platelet counts ≥50 × 109/L. The randomized JAKARTA phase 3 trial and nonrandomized JAKARTA-2 phase 2 trial consistently showed that fedratinib attenuated symptoms and splenomegaly in patients with ruxolitinib-resistant or intolerant intermediate-1, intermediate-2, or high-risk myelofibrosis. In addition, Harrison, C. N. et al. conducted a phase 2 multicenter study and reported that treatment with 400 mg fedratinib resulted in remarkable reductions in spleen volume and clinical symptoms in ~30% of patients with myelofibrosis that was resistant or intolerant to ruxolitinib. However, fedratinib was reported to cause Wernicke’s encephalopathy, confirmed by magnetic resonance imaging, in 8 of 670 patients that received fedratinib treatment and in 4 women who received 500 mg/day fedratinib in the JAKARTA trial, which raised concerns and hampered the further clinical development of fedratinib. Anemia and thrombocytopenia were also observed in patients that received fedratinib treatment in both the JAKARTA trial and the JAKARTA-2 trial. Decernotinib, a JAK3-selective inhibitor, is currently under development and considered efficacious against RA., The previous phase 2a and 2b trials both reported that decernotinib, as a monotherapy or in combination with methotrexate, contributed to the improved signs and symptoms of RA patients with inadequate response to methotrexate.– The major adverse effects seen in those trials included headache; nausea; elevated levels of transaminases, lipoproteins, and creatinine; and reduced numbers of lymphocytes and neutrophils. Itacitinib, a novel selective JAK1 inhibitor, has a wide range of anti-inflammatory activities. Thus far, itacitinib has been primarily used for the treatment of graft-versus-host disease (GVHD). A multicenter phase 2 trial (NCT03846479) recently reported that patients with low-risk acute GVHD administered 28 days of itacitinib without the conventional administration of systemic corticosteroids (SCSs) achieved effective drug response rates and reduced symptomatic flares. A phase 3 trial (GRAVITAS-301, NCT03139604) demonstrated that itacitinib, in combination with corticosteroids, did not attain the expected improvement in the overall response rate (ORR) at day 28 among patients with acute GVHD. The European Society for Blood and Bone Marrow Transplantation (EBMT 2022) reported the preliminary results of a phase 2 trial (NCT 04071366), stating that itacitinib exhibited good performance in the prevention of cytokine release syndrome (CRS) following by immunotherapies. Moreover, the World Congress of lung cancer (WCLC 2022) presented that patients with NSCLC with high PD-L1 expression (≥50%) had a favorable profile of efficacy and tolerance after 6 weeks of treatment with a combination of itacitinib and pembrolizumab. The most common adverse events mainly included decreased platelet and neutrophil counts, anemia, and hyperglycemia. Further studies are needed to obtain further insights into the use of itacitinib for the treatment of acute GVHD.

Currently, several JAK inhibitors in different phases of clinical trials are being explored to expand potential indications, increase drug adherence and achieve better safety. For example, upadacitinib (ABT‐494) is a potent and selective JAK1 inhibitor that received FDA approval for clinical use in patients with moderate-to-severe RA, psoriatic arthritis (PsA), ankylosing spondylitis (AS) and non-radiographic axial spondylarthritis (nr-axSpA).– The SELECT-MONOTHERAPY study found that upadacitinib monotherapy improved the clinical symptoms when administered in combination with stable background csDMARDs in patients with moderate-to-severe active RA. Two classical phase 3 trials (SELECT-PsA 1 and SELECT-PsA 2) conducted in patients with PsA who had an inadequate or intolerant response to one or more TNF inhibitors found that upadacitinib reduced the PsA disease severity compared with placebo or adalimumab., Furthermore, upadacitinib was found to be effective in patients with active AS who had a bDMARD-inadequate response during a 14-week treatment period. In the SELECT-AXIS 2 trial, upadacitinib alleviated the painful symptoms of nr-axSpA as compared with placebo at week 14. Recently, the European Union passed approval for upadacitinib treatment to be developed for patients with inflammatory bowel disease based on positive clinical outcomes in two induction studies (U-ACHIEVE and U-ACCOMPLISH) and a maintenance study (U-ACHIEVE). Nonetheless, additional trials with large population samples are required to validate the long-term safety of upadacitinib, because other JAK inhibitors with similar mechanisms have reported adverse events such as cardiovascular events, embolism and thrombosis, cancer and even death.

Abrocitinib, another FDA-approved JAK1 selective inhibitor being developed for AD treatment, functions by blocking several critical cytokines, including IL-4, IL-13, IL-22, and IL-31, that participate in the pathology of AD., In a series of phase 3 trials (JADE Mono-1, MONO-2, TEEN, COMPARE, EXTEND, and REGIMEN), abrocitinib monotherapy achieved marked amelioration of pruritus and AD disease severity, resulting in the expansion of indications for abrocitinib administration to adolescents aged 12–17 years having moderate-to-severe AD.,,,– Furthermore, the rapid improvement of pruritus produced by abrocitinib supports treatment compliance, which further validates the safety and tolerability of abrocitinib in patients with moderate-to-severe AD. Abrocitinib has manageable safety, and its common adverse events include nausea, headache, acne and reduced platelet counts., Therefore, its benefit-to-harm ratio needs to be thoroughly investigated before it can be used for the long-term treatment of AD. Strikingly, deucravacitinib (BMS-986165), by producing a distinctively allosteric mechanism to combine with the TYK2 regulatory domain and not influence the functions of JAK1/2/3, became the first oral agent that was used to treat psoriasis with a favorable safety profile. Deucravacitinib is also the first approved TYK2 selective inhibitor for the treatment of moderate-to-severe plaque psoriasis; it was approved in September 2022 by the USA FDA and then approved in Japan for plaque, generalized pustular, and erythrodermic psoriasis. The two crucial phase 3 POETYK PSO-1 and POETYK PSO-2 trials have proven the superior performance of deucravacitinib against moderate-to-severe plaque psoriasis in terms of multiple efficacy endpoints compared with placebo or apremilast., Moreover, enduring symptom remission was still maintained at 52 weeks of continuous treatment with deucravacitinib. The most common adverse events of deucravacitinib include mild-to-moderate nasopharyngitis and upper respiratory tract infections. The recently announced POETYK PSO-3 trial broadens the exploration of the efficacy of deucravacitinib in Asian populations for the first time. The oral results of the 30th European Academy of Dermatology and Venereology (EADV) Congress demonstrated that the administration of deucravacitinib to patients with moderate-to-severe Asian plaque psoriasis results in sustained efficacy and even favorable efficacy for refractory scalp psoriasis. Meanwhile, the efficacy and safety of deucravacitinib in a variety of immune-related diseases, including psoriatic arthritis (PsA), systemic lupus erythematosus, and inflammatory bowel disease, is also under exploration in multiple large clinical trials.

In recent years, several independently developed Chinese JAK inhibitors (e.g., including jaktinib, golidocitinib, ivarmactinib, and itacitinib) under different phases of clinical trials are being considered to have great clinical potential.– In October 2022, Jaktinib, a deuterated compound of momelotinib that widely inhibits JAK1, JAK2, JAK3, TYK2 and ACVR1, became the first approved domestic JAK inhibitor for the treatment of moderate-to-severe myelofibrosis., A published phase 2 trial has shown that jaktinib reduced the spleen size and alleviated the clinical symptoms of patients with moderate-to-severe myelofibrosis. It was evident that jaktinib was well-tolerated and that anemia and thrombocytopenia were the most common adverse events. The phase 3 trial (NCT04617028) further reported the encouraging efficacy of jaktinib in the treatment of myelofibrosis, with remarkable improvement of the symptoms, anemia and spleen volume when compared with hydroxyurea. Based on the reported existing efficacy and safety, approvals were needed for conducting clinical trials on the use of jaktinib in a series of diseases, such as COVID-19, AD, systemic lupus erythematosus, alopecia areata, and mild-to-moderate psoriasis.

Overall, JAK inhibitors offer great promise as targeted therapies. However, sufficient real-world evidence is required to fully explore their long-term safety, durability and effectiveness.

Current challenges and directions in the field

A sophisticated understanding of JAK-STAT signaling has provided many insights into the development of novel drugs.– However, many challenges remain for improving target selectivity in JAK-STAT signaling, and exploration of the long-term safety of the developed agents is still required. Each JAK inhibitor impedes the combination of a JAK enzyme with ATP through the highly selective ATP-binding pocket., The Michaelis equilibrium of ATP, JAK enzyme and JAK inhibitor shows that the combination of JAK with its substrate is affected by the intracellular drug concentration and drug selectivity. However, drug concentrations depend on multiple factors, such as the patient’s age, body weight, liver and renal function and drug interactions, and it has been challenging to achieve absolute selectivity in terms of JAK inhibitors., More selective JAK inhibitors are being developed to reduce their unwanted effects on cytokine functions and further improve the overall safety and efficacy.– For example, the JAK inhibitors abrocitinib and delgocitinib are currently being further developed to optimize treatment efficiency with minimum off-target effects.

Combination therapies using JAK inhibitors combined with other immunomodulatory or anti-inflammatory agents are an emerging approach; these are also being explored to achieve maximum treatment response with few adverse events., The simultaneous inhibition of the JAK-STAT signaling pathway and other potential targets appears to be another feasible option for drug development. For example, fedratinib, an innovative JAK inhibitor that simultaneously targets the activities of JAK2 and Fms-like tyrosine kinase 3 (FLT3) with crucial effects on the survival and proliferation of primitive hematopoietic progenitor cells, has been approved as an oral treatment for intermediate or high-risk myelofibrosis.–

The topical or inhalational application of JAK inhibitors is another exciting area of research in multiple ongoing animal models and larger clinical trials., The intestinally restricted pan-JAK inhibitor TD-1473 is expected to soon become available to treat inflammatory bowel disease with fewer systemic adverse side effects than other treatment options. The ongoing development and approval of emerging JAK inhibitors in preclinical studies and clinical settings will provide optimized JAK inhibitors as potent therapeutic options for a range of diseases in the future.

Conclusions

As a primarily canonical signaling pathway, the JAK-STAT signaling pathway transduces cytokine-activated extracellular signals to the nucleus to mediate gene expression, thus exerting indispensable functions in a series of cellular processes, particularly ones with immunomodulatory effects. Abnormal activation of JAK-STAT signaling is central to the initiation and progression of many diseases, especially immune-related diseases, and cancers. Drugs that target the JAK-STAT pathway have been approved by the FDA as alternative treatments for certain diseases and have exhibited powerful clinical benefits. A substantial number of novel agents targeting the JAK-STAT pathway are currently under development, yet there is still little evidence of differences in efficacy between selective JAK inhibitors and pan-selective JAK inhibitors. Explorations of the use of JAK inhibitors in early disease stages and in combination with other conventional drugs are also currently in progress. Recent studies have shown that a portion of patients are unresponsive to JAK inhibitors and have tried to unveil the relevant drug resistance mechanisms. Future research should offer comprehensive insights into the physiological and pathogenic mechanisms of the JAK-STAT pathway in disease development and aim to identify biomarkers to assess the long-term efficacy and safety of JAK inhibitors and to optimize the therapeutic efficacy of JAK inhibitors in patients with different stages and severity of disease to achieve individualized treatment. Overall, understanding the associations of the JAK-STAT pathway with immune regulation and disease progression will provide new therapeutic strategies to treat diverse diseases, particularly immune-related diseases, and cancer.

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  28. 28.

    Tzeng HT, Chyuan IT, Lai JH. Targeting the JAK-STAT pathway in autoimmune diseases and cancers: a focus on molecular mechanisms and therapeutic potential. Biochem. Pharm. 2021;193:114760.

    Not in our library10.1016/j.bcp.2021.114760

  29. 29.

    Lai SY, Johnson FM. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: implications for future therapeutic approaches. Drug Resist. Updat. 2010;13:67-78.

    Not in our library10.1016/j.drup.2010.04.001

  30. 30.

    Burmester GR, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381:451-460.

    Not in our library10.1016/s0140-6736(12)61424-x

  31. 31.

    Chan JM, et al. Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling. Science. 2022;377:1180-1191.

    Not in our library10.1126/science.abn0478

  32. 32.

    Boyle DL, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann. Rheum. Dis. 2015;74:1311-1316.

    Not in our library10.1136/annrheumdis-2014-206028

  33. 33.

    Palmroth M, et al. Tofacitinib suppresses several JAK-STAT pathways in rheumatoid arthritis in vivo and baseline signaling profile associates with treatment response. Front. Immunol. 2021;12:738481.

    Not in our library10.3389/fimmu.2021.738481

  34. 34.

    Tucci G, et al. Baricitinib therapy response in rheumatoid arthritis patients associates to STAT1 phosphorylation in monocytes. Front. Immunol. 2022;13:932240.

    Not in our library10.3389/fimmu.2022.932240

  35. 35.

    Verstovsek S, et al. A phase I, open-label, dose-escalation, multicenter study of the JAK2 inhibitor NS-018 in patients with myelofibrosis. Leukemia. 2017;31:393-402.

    Not in our library10.1038/leu.2016.215

  36. 36.

    Benucci M, et al. Cardiovascular safety, cancer and Jak-inhibitors: differences to be highlighted. Pharm. Res. 2022;183:106359.

    Not in our library10.1016/j.phrs.2022.106359

  37. 37.

    Desai RJ, Pawar A, Weinblatt ME, Kim SC. Comparative risk of venous thromboembolism in rheumatoid arthritis patients receiving tofacitinib versus those receiving tumor necrosis factor inhibitors: an observational cohort study. Arthritis Rheumatol. 2019;71:892-900.

    Not in our library10.1002/art.40798

  38. 38.

    O’Shea JJ, et al. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med. 2015;66:311-328.

    Not in our library10.1146/annurev-med-051113-024537

  39. 39.

    Singh SR, Chen X, Hou SX. JAK/STAT signaling regulates tissue outgrowth and male germline stem cell fate in Drosophila. Cell Res. 2005;15:1-5.

    Not in our library10.1038/sj.cr.7290255

  40. 40.

    Fahmideh H, et al. The role of natural products as inhibitors of JAK/STAT signaling pathways in glioblastoma treatment. Oxid. Med Cell Longev. 2022;2022:7838583.

    Not in our library10.1155/2022/7838583

  41. 41.

    Gordon, M. J., Smith, M. R., Nastoupil, L. J. Follicular lymphoma: the long and winding road leading to your cure? Blood Rev. 57, 100992 (2022).

    Not in our library10.1016/j.blre.2022.100992

  42. 42.

    Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs. 2017;77:521-546.

    Not in our library10.1007/s40265-017-0701-9

  43. 43.

    Villarino AV, Kanno Y, O’Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 2017;18:374-384.

    Not in our library10.1038/ni.3691

  44. 44.

    Waldmann TA, Chen J. Disorders of the JAK/STAT pathway in T cell lymphoma pathogenesis: implications for immunotherapy. Annu. Rev. Immunol. 2017;35:533-550.

    Not in our library10.1146/annurev-immunol-110416-120628

  45. 45.

    Roskoski R. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharm. Res. 2016;111:784-803.

    Not in our library10.1016/j.phrs.2016.07.038

  46. 46.

    Yin T, Yang L, Yang YC. Tyrosine phosphorylation and activation of JAK family tyrosine kinases by interleukin-9 in MO7E cells. Blood. 1995;85:3101-3106.

    Not in our library10.1182/blood.v85.11.3101.bloodjournal85113101

  47. 47.

    Choudhury GG, Marra F, Kiyomoto H, Abboud HE. PDGF stimulates tyrosine phosphorylation of JAK 1 protein tyrosine kinase in human mesangial cells. Kidney Int. 1996;49:19-25.

    Not in our library10.1038/ki.1996.3

  48. 48.

    Miyazaki T, et al. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science. 1994;266:1045-1047.

    Not in our library10.1126/science.7973659

  49. 49.

    Russell SM, et al. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994;266:1042-1045.

    Not in our library10.1126/science.7973658

  50. 50.

    Saijo K, Park SY, Ishida Y, Arase H, Saito T. Crucial role of Jak3 in negative selection of self-reactive T cells. J. Exp. Med. 1997;185:351-356.

    Not in our library10.1084/jem.185.2.351

  51. 51.

    Das Gupta D, et al. IRF4 deficiency vulnerates B-cell progeny for leukemogenesis via somatically acquired Jak3 mutations conferring IL-7 hypersensitivity. Cell Death Differ. 2022;29:2163-2176.

    Not in our library10.1038/s41418-022-01005-z

  52. 52.

    Liao W, et al. Opposing actions of IL-2 and IL-21 on Th9 differentiation correlate with their differential regulation of BCL6 expression. Proc. Natl. Acad. Sci. USA. 2014;111:3508-3513.

    Not in our library10.1073/pnas.1301138111

  53. 53.

    Malka Y, et al. Ligand-independent homomeric and heteromeric complexes between interleukin-2 or -9 receptor subunits and the gamma chain. J. Biol. Chem. 2008;283:33569-33577.

    Not in our library10.1074/jbc.m803125200

  54. 54.

    Degryse S, et al. JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model. Blood. 2014;124:3092-3100.

    Not in our library10.1182/blood-2014-04-566687

  55. 55.

    Barcia Durán JG, et al. Endothelial Jak3 expression enhances pro-hematopoietic angiocrine function in mice. Commun. Biol. 2021;4:406.

    Not in our library10.1038/s42003-021-01846-3

  56. 56.

    Glassman CR, et al. Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation. Science. 2022;376:163-169.

    Not in our library10.1126/science.abn8933

  57. 57.

    Ferrao R, Lupardus PJ. The Janus Kinase (JAK) FERM and SH2 Domains: Bringing Specificity to JAK-Receptor Interactions. Front. Endocrinol. (Lausanne). 2017;8:71.

    Not in our library10.3389/fendo.2017.00071

  58. 58.

    Zhou YJ, et al. Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases. Mol. Cell. 2001;8:959-969.

    Not in our library10.1016/s1097-2765(01)00398-7

  59. 59.

    Goult BT, et al. Structure of a double ubiquitin-like domain in the talin head: a role in integrin activation. EMBO J. 2010;29:1069-1080.

    Not in our library10.1038/emboj.2010.4

  60. 60.

    Lupardus PJ, et al. Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition. Proc. Natl Acad. Sci. USA. 2014;111:8025-8030.

    Not in our library10.1073/pnas.1401180111

  61. 61.

    Bandaranayake RM, et al. Crystal structures of the JAK2 pseudokinase domain and the pathogenic mutant V617F. Nat. Struct. Mol. Biol. 2012;19:754-759.

    Not in our library10.1038/nsmb.2348

  62. 62.

    Barahmand-Pour F, Meinke A, Groner B, Decker T. Jak2-Stat5 interactions analyzed in yeast. J. Biol. Chem. 1998;273:12567-12575.

    Not in our library10.1074/jbc.273.20.12567

  63. 63.

    Guschin D, et al. A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin-6. EMBO J. 1995;14:1421-1429.

    Not in our library10.1002/j.1460-2075.1995.tb07128.x

  64. 64.

    Finbloom DS, Winestock KD. IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J. Immunol. 1995;155:1079-1090.

    Not in our library10.4049/jimmunol.155.3.1079

  65. 65.
    The influenza virus PB2 protein evades antiviral innate immunity by inhibiting JAK1/STAT signalling · 2022
    Not checked
  66. 66.

    Shao T, et al. Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression. Cell Mol. Immunol. 2022;19:1130-1140.

    Not in our library10.1038/s41423-022-00904-y

  67. 67.

    Gerlach K, et al. The JAK1/3 inhibitor tofacitinib suppresses T cell homing and activation in chronic intestinal inflammation. J. Crohns Colitis. 2020;18:jjaa162.

    Not in our library10.1093/ecco-jcc/jjaa162

  68. 68.

    Lee TS, et al. Mechanisms of constitutive activation of Janus kinase 2-V617F revealed at the atomic level through molecular dynamics simulations. Cancer. 2009;115:1692-1700.

    Not in our library10.1002/cncr.24183

  69. 69.

    Roskoski R. Janus kinase (JAK) inhibitors in the treatment of neoplastic and inflammatory disorders. Pharm. Res. 2022;183:106362.

    Not in our library10.1016/j.phrs.2022.106362

  70. 70.

    Liosi ME, et al. Insights on JAK2 modulation by potent, selective, and cell-permeable pseudokinase-domain ligands. J. Med. Chem. 2022;65:8380-8400.

    Not in our library10.1021/acs.jmedchem.2c00283

  71. 71.

    Rai S, et al. Inhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm. Nat. Commun. 2022;13:5346.

    Not in our library10.1038/s41467-022-32927-4

  72. 72.

    Rahman MF, et al. Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm. Nat. Commun. 2022;13:5347.

    Not in our library10.1038/s41467-022-32928-3

  73. 73.

    Neubauer H, et al. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell. 1998;93:397-409.

    Not in our library10.1016/s0092-8674(00)81168-x

  74. 74.

    Mu W, Ao J, Li Y, Zhang J, Duan C. Exploring the protective mechanisms of total tannins from Geum japonicum var. chinense F.Bolle in mice with hematopoietic dysfunction via the JAK2/STAT3/5 signaling pathway. J. Ethnopharmacol. 2022;296:115507.

    Not in our library10.1016/j.jep.2022.115507

  75. 75.

    Rubio T, Viana R, Moreno-Estellés M, Campos-Rodríguez Á, Sanz P. TNF and IL6/Jak2 signaling pathways are the main contributors of the glia-derived neuroinflammation present in Lafora disease, a fatal form of progressive myoclonus epilepsy. Neurobiol. Dis. 2023;176:105964.

    Not in our library10.1016/j.nbd.2022.105964

  76. 76.
    The JAK/STAT signaling pathway: from bench to clinic · 2021
    No notice
  77. 77.

    Dodington DW, Desai HR, Woo M. JAK/STAT - emerging players in metabolism. Trends Endocrinol. Metab. 2018;29:55-65.

    Not in our library10.1016/j.tem.2017.11.001

  78. 78.

    DiSanto JP. Cytokines: shared receptors, distinct functions. Curr. Biol. 1997;7:R424-R426.

    Not in our library10.1016/s0960-9822(06)00208-9

  79. 79.

    Schindler C, Darnell JE. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu. Rev. Biochem. 1995;64:621-651.

    Not in our library10.1146/annurev.bi.64.070195.003201

  80. 80.

    Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O. Signaling through the hematopoietic cytokine receptors. Annu. Rev. Immunol. 1995;13:369-398.

    Not in our library10.1146/annurev.iy.13.040195.002101

  81. 81.

    Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science. 1995;270:794-797.

    Not in our library10.1126/science.270.5237.794

  82. 82.

    Karaghiosoff M, et al. Partial impairment of cytokine responses in Tyk2-deficient mice. Immunity. 2000;13:549-560.

    Not in our library10.1016/s1074-7613(00)00054-6

  83. 83.

    Rusiñol L, Puig L. Tyk2 targeting in immune-mediated inflammatory diseases. Int J. Mol. Sci. 2023;24:3391.

    Not in our library10.3390/ijms24043391

  84. 84.

    Liau NPD, et al. Enzymatic characterization of wild-type and mutant janus kinase 1. Cancers (Basel). 2019;11:1701.

    Not in our library10.3390/cancers11111701

  85. 85.

    Gauzzi MC, et al. The amino-terminal region of Tyk2 sustains the level of interferon alpha receptor 1, a component of the interferon alpha/beta receptor. Proc. Natl Acad. Sci. USA. 1997;94:11839-11844.

    Not in our library10.1073/pnas.94.22.11839

  86. 86.

    Velazquez L, et al. Distinct domains of the protein tyrosine kinase tyk2 required for binding of interferon-alpha/beta and for signal transduction. J. Biol. Chem. 1995;270:3327-3334.

    Not in our library10.1074/jbc.270.7.3327

  87. 87.

    Stahl N, et al. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science. 1994;263:92-95.

    Not in our library10.1126/science.8272873

  88. 88.

    Bacon CM, et al. Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2: differential use of Janus family tyrosine kinases by IL-2 and IL-12. J. Exp. Med. 1995;181:399-404.

    Not in our library10.1084/jem.181.1.399

  89. 89.

    Welham MJ, Learmonth L, Bone H, Schrader JW. Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin. J. Biol. Chem. 1995;270:12286-12296.

    Not in our library10.1074/jbc.270.20.12286

  90. 90.

    Watford WT, O’Shea JJ. Human tyk2 kinase deficiency: another primary immunodeficiency syndrome. Immunity. 2006;25:695-697.

    Not in our library10.1016/j.immuni.2006.10.007

  91. 91.

    Verhoeven Y, et al. The potential and controversy of targeting STAT family members in cancer. Semin. Cancer Biol. 2020;60:41-56.

    Not in our library10.1016/j.semcancer.2019.10.002

  92. 92.
    STAT inhibitors for cancer therapy · 2013
    No notice
  93. 93.

    Dorritie KA, McCubrey JA, Johnson DE. STAT transcription factors in hematopoiesis and leukemogenesis: opportunities for therapeutic intervention. Leukemia. 2014;28:248-257.

    Not in our library10.1038/leu.2013.192

  94. 94.

    Zhang T, Kee WH, Seow KT, Fung W, Cao X. The coiled-coil domain of Stat3 is essential for its SH2 domain-mediated receptor binding and subsequent activation induced by epidermal growth factor and interleukin-6. Mol. Cell Biol. 2000;20:7132-7139.

    Not in our library10.1128/mcb.20.19.7132-7139.2000

  95. 95.

    Kwock JT, et al. IL-27 signaling activates skin cells to induce innate antiviral proteins and protects against Zika virus infection. Sci. Adv. 2020;6:eaay3245.

    Not in our library10.1126/sciadv.aay3245

  96. 96.

    Léger T, Balaguer P, Le Hégarat L, Fessard V. Fate and PPARγ and STATs-driven effects of the mitochondrial complex I inhibitor tebufenpyrad in liver cells revealed with multi-omics. J. Hazard Mater. 2023;442:130083.

    Not in our library10.1016/j.jhazmat.2022.130083

  97. 97.

    Lu, C. et al. IFNGR/STAT1 signaling in recipient hematopoietic antigen presenting cells suppresses graft-versus-host disease. J. Clin. Invest.133, e125986 (2022).

    Not in our library10.1172/jci125986

  98. 98.

    Wang J, et al. Leukemia inhibitory factor protects against graft-versus-host disease while preserving graft-versus-leukemia activity. Blood. 2022;140:2076-2090.

    Not in our library10.1182/blood.2022015677

  99. 99.

    Qin Y, et al. Age-associated B cells contribute to the pathogenesis of rheumatoid arthritis by inducing activation of fibroblast-like synoviocytes via TNF-α-mediated ERK1/2 and JAK-STAT1 pathways. Ann. Rheum. Dis. 2022;81:1504-1514.

    Not in our library10.1136/ard-2022-222605

  100. 100.

    Pelham SJ, et al. STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis. J. Allergy Clin. Immunol. 2022;150:931-946.

    Not in our library10.1016/j.jaci.2022.04.011

  101. 101.

    Duetsch G, et al. STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study. Hum. Mol. Genet. 2002;11:613-621.

    Not in our library10.1093/hmg/11.6.613

  102. 102.

    Schindler C, Levy DE, Decker T. JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 2007;282:20059-20063.

    Not in our library10.1074/jbc.r700016200

  103. 103.

    Chen H, et al. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell. 2011;147:436-446.

    Not in our library10.1016/j.cell.2011.09.022

  104. 104.

    Drube, S. et al. Interleukin-3 stabilizes CD124/IL-4α surface expression in mast cells via Tyk2 and STAT6. Immunology.169, 102–112 (2022).

    Not in our library10.1111/imm.13614

  105. 105.

    Hoey T, Schindler U. STAT structure and function in signaling. Curr. Opin. Genet. Dev. 1998;8:582-587.

    Not in our library10.1016/s0959-437x(98)80015-4

  106. 106.

    Shuai K. The STAT family of proteins in cytokine signaling. Prog. Biophys. Mol. Biol. 1999;71:405-422.

    Not in our library10.1016/s0079-6107(98)00051-0

  107. 107.

    Li WX. Canonical and non-canonical JAK-STAT signaling. Trends Cell Biol. 2008;18:545-551.

    Not in our library10.1016/j.tcb.2008.08.008

  108. 108.

    Baldini C, Moriconi FR, Galimberti S, Libby P, De Caterina R. The JAK-STAT pathway: an emerging target for cardiovascular disease in rheumatoid arthritis and myeloproliferative neoplasms. Eur. Heart J. 2021;42:4389-4400.

    Not in our library10.1093/eurheartj/ehab447

  109. 109.

    Xin P, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int. Immunopharmacol. 2020;80:106210.

    Not in our library10.1016/j.intimp.2020.106210

  110. 110.

    Hong J, et al. PRC2-mediated epigenetic suppression of Type I IFN-STAT2 signaling impairs antitumor immunity in luminal breast cancer. Cancer Res. 2022;82:4624-4640.

    Not in our library10.1158/0008-5472.can-22-0736

  111. 111.

    Gothe F, et al. Aberrant inflammatory responses to type I interferon in STAT2 or IRF9 deficiency. J. Allergy Clin. Immunol. 2022;150:955-964.e916.

    Not in our library10.1016/j.jaci.2022.01.026

  112. 112.

    Li YJ, Zhang C, Martincuks A, Herrmann A, Yu H. STAT proteins in cancer: orchestration of metabolism. Nat. Rev. Cancer. 2023;23:115-134.

    Not in our library10.1038/s41568-022-00537-3

  113. 113.

    Shih PC. The role of the STAT3 signaling transduction pathways in radioresistance. Pharm. Ther. 2022;234:108118.

    Not in our library10.1016/j.pharmthera.2022.108118

  114. 114.

    Zhang L, et al. Signal transducer and activator of transcription 3 signaling in tumor immune evasion. Pharm. Ther. 2022;230:107969.

    Not in our library10.1016/j.pharmthera.2021.107969

  115. 115.

    Yoshimura A, Yasukawa H. JAK’s SOCS: a mechanism of inhibition. Immunity. 2012;36:157-159.

    Not in our library10.1016/j.immuni.2012.01.010

  116. 116.

    Linossi EM, et al. Discovery of an exosite on the SOCS2-SH2 domain that enhances SH2 binding to phosphorylated ligands. Nat. Commun. 2021;12:7032.

    Not in our library10.1038/s41467-021-26983-5

  117. 117.

    Durham GA, Williams JJL, Nasim MT, Palmer TM. Targeting SOCS proteins to control JAK-STAT signalling in disease. Trends Pharm. Sci. 2019;40:298-308.

    Not in our library10.1016/j.tips.2019.03.001

  118. 118.
    The molecular basis of JAK/STAT inhibition by SOCS1 · 2018
    No notice
  119. 119.

    Rico-Bautista E, Flores-Morales A, Fernández-Pérez L. Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine Growth Factor Rev. 2006;17:431-439.

    Not in our library10.1016/j.cytogfr.2006.09.008

  120. 120.

    Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 2007;7:454-465.

    Not in our library10.1038/nri2093

  121. 121.

    Starr R, et al. A family of cytokine-inducible inhibitors of signalling. Nature. 1997;387:917-921.

    Not in our library10.1038/43206

  122. 122.

    Liang Y, Xu WD, Peng H, Pan HF, Ye DQ. SOCS signaling in autoimmune diseases: molecular mechanisms and therapeutic implications. Eur. J. Immunol. 2014;44:1265-1275.

    Not in our library10.1002/eji.201344369

  123. 123.

    Alexander WS, et al. Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction. J. Leukoc. Biol. 1999;66:588-592.

    Not in our library10.1002/jlb.66.4.588

  124. 124.

    Kishimoto T, Kikutani H. Knocking the SOCS off a tumor suppressor. Nat. Genet. 2001;28:4-5.

    Not in our library10.1038/ng0501-4

  125. 125.

    Thomas SJ, Snowden JA, Zeidler MP, Danson SJ. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. Br. J. Cancer. 2015;113:365-371.

    Not in our library10.1038/bjc.2015.233

  126. 126.
    The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells · 2017
    No notice
  127. 127.

    Wu CS, Zou L. The SUMO (small ubiquitin-like modifier) ligase PIAS3 primes ATR for checkpoint activation. J. Biol. Chem. 2016;291:279-290.

    Not in our library10.1074/jbc.m115.691170

  128. 128.

    Rytinki MM, Kaikkonen S, Pehkonen P, Jääskeläinen T, Palvimo JJ. PIAS proteins: pleiotropic interactors associated with SUMO. Cell Mol. Life Sci. 2009;66:3029-3041.

    Not in our library10.1007/s00018-009-0061-z

  129. 129.

    Frankson R, et al. Therapeutic targeting of oncogenic tyrosine phosphatases. Cancer Res. 2017;77:5701-5705.

    Not in our library10.1158/0008-5472.can-17-1510

  130. 130.

    Pike KA, Tremblay ML. Protein tyrosine phosphatases: regulators of CD4 T cells in inflammatory bowel disease. Front. Immunol. 2018;9:2504.

    Not in our library10.3389/fimmu.2018.02504

  131. 131.

    Long D, Chen Y, Wu H, Zhao M, Lu Q. Clinical significance and immunobiology of IL-21 in autoimmunity. J. Autoimmun. 2019;99:1-14.

    Not in our library10.1016/j.jaut.2019.01.013

  132. 132.

    Yan Z, Gibson SA, Buckley JA, Qin H, Benveniste EN. Role of the JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory diseases. Clin. Immunol. 2018;189:4-13.

    Not in our library10.1016/j.clim.2016.09.014

  133. 133.

    Roxburgh CS, McMillan DC. Therapeutics targeting innate immune/inflammatory responses through the interleukin-6/JAK/STAT signal transduction pathway in patients with cancer. Transl. Res. 2016;167:61-66.

    Not in our library10.1016/j.trsl.2015.08.013

  134. 134.

    O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36:542-550.

    Not in our library10.1016/j.immuni.2012.03.014

  135. 135.

    O’Shea JJ, Murray PJ. Cytokine signaling modules in inflammatory responses. Immunity. 2008;28:477-487.

    Not in our library10.1016/j.immuni.2008.03.002

  136. 136.

    Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415-1421.

    Not in our library10.1126/science.8197455

  137. 137.

    Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat. Rev. Rheumatol. 2016;12:25-36.

    Not in our library10.1038/nrrheum.2015.167

  138. 138.

    O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med. 2013;368:161-170.

    Not in our library10.1056/nejmra1202117

  139. 139.

    Costa-Pereira AP, et al. Mutational switch of an IL-6 response to an interferon-gamma-like response. Proc. Natl Acad. Sci. USA. 2002;99:8043-8047.

    Not in our library10.1073/pnas.122236099

  140. 140.

    O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann. Rheum. Dis. 2013;72:ii111-ii115.

    Not in our library10.1136/annrheumdis-2012-202576

  141. 141.

    Kang YH, Biswas A, Field M, Snapper SB. STAT1 signaling shields T cells from NK cell-mediated cytotoxicity. Nat. Commun. 2019;10:912.

    Not in our library10.1038/s41467-019-08743-8

  142. 142.

    Putz EM, et al. CDK8-mediated STAT1-S727 phosphorylation restrains NK cell cytotoxicity and tumor surveillance. Cell Rep. 2013;4:437-444.

    Not in our library10.1016/j.celrep.2013.07.012

  143. 143.

    Watford WT, et al. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol. Rev. 2004;202:139-156.

    Not in our library10.1111/j.0105-2896.2004.00211.x

  144. 144.

    Boudreau JE, et al. IL-15 and type I interferon are required for activation of tumoricidal NK cells by virus-infected dendritic cells. Cancer Res. 2011;71:2497-2506.

    Not in our library10.1158/0008-5472.can-10-3025

  145. 145.
    An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs · 2021
    Corrected
  146. 146.

    Goropevšek A, Holcar M, Avčin T. The role of STAT signaling pathways in the pathogenesis of systemic lupus erythematosus. Clin. Rev. Allergy Immunol. 2017;52:164-181.

    Not in our library10.1007/s12016-016-8550-y

  147. 147.

    Park JS, et al. STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis Rheumatol. 2014;66:918-929.

    Not in our library10.1002/art.38305

  148. 148.

    Ma CS, et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood. 2012;119:3997-4008.

    Not in our library10.1182/blood-2011-11-392985

  149. 149.

    Gracey E, et al. TYK2 inhibition reduces type 3 immunity and modifies disease progression in murine spondyloarthritis. J. Clin. Invest. 2020;130:1863-1878.

    Not in our library10.1172/jci126567

  150. 150.

    Sigurdsson S, et al. Polymorphisms in the tyrosine kinase 2 and interferon regulatory factor 5 genes are associated with systemic lupus erythematosus. Am. J. Hum. Genet. 2005;76:528-537.

    Not in our library10.1086/428480

  151. 151.

    Ellinghaus D, et al. Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci. Am. J. Hum. Genet. 2012;90:636-647.

    Not in our library10.1016/j.ajhg.2012.02.020

  152. 152.

    Casaca VI, et al. STAT6 polymorphisms are associated with neonatal regulatory T cells and cytokines and atopic diseases at 3 years. Allergy. 2013;68:1249-1258.

    Not in our library10.1111/all.12220

  153. 153.

    Fabre A, et al. Clinical aspects of STAT3 gain-of-function germline mutations: a systematic review. J. Allergy Clin. Immunol. Pr. 2019;7:1958-1969.e1959.

    Not in our library10.1016/j.jaip.2019.02.018

  154. 154.

    Lundgren S, et al. Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia. Leukemia. 2021;35:1365-1379.

    Not in our library10.1038/s41375-021-01231-3

  155. 155.

    Marabelle A, Aspeslagh S, Postel-Vinay S, Soria JC. JAK mutations as escape mechanisms to anti-PD-1 therapy. Cancer Disco. 2017;7:128-130.

    Not in our library10.1158/2159-8290.cd-16-1439

  156. 156.

    Jehanno C, Vulin M, Richina V, Richina F, Bentires-Alj M. Phenotypic plasticity during metastatic colonization. Trends Cell Biol. 2022;32:854-867.

    Not in our library10.1016/j.tcb.2022.03.007

  157. 157.

    Westneat DF, Potts LJ, Sasser KL, Shaffer JD. Causes and consequences of phenotypic plasticity in complex environments. Trends Ecol. Evol. 2019;34:555-568.

    Not in our library10.1016/j.tree.2019.02.010

  158. 158.

    Bakir B, Chiarella AM, Pitarresi JR, Rustgi AK. EMT, MET, plasticity, and tumor metastasis. Trends Cell Biol. 2020;30:764-776.

    Not in our library10.1016/j.tcb.2020.07.003

  159. 159.

    Burkhardt DB, et al. Mapping phenotypic plasticity upon the cancer cell state landscape using manifold learning. Cancer Discov. 2022;12:1847-1859.

    Not in our library10.1158/2159-8290.cd-21-0282

  160. 160.

    Lee YI, et al. WNT5A drives interleukin-6-dependent epithelial-mesenchymal transition via the JAK/STAT pathway in keloid pathogenesis. Burns Trauma. 2022;10:tkac023.

    Not in our library10.1093/burnst/tkac023

  161. 161.

    Quintanal-Villalonga Á, et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance. Nat. Rev. Clin. Oncol. 2020;17:360-371.

    Not in our library10.1038/s41571-020-0340-z

  162. 162.

    Yu HA, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res. 2013;19:2240-2247.

    Not in our library10.1158/1078-0432.ccr-12-2246

  163. 163.

    Beebe K, Lee WC, Micchelli CA. JAK/STAT signaling coordinates stem cell proliferation and multilineage differentiation in the Drosophila intestinal stem cell lineage. Dev. Biol. 2010;338:28-37.

    Not in our library10.1016/j.ydbio.2009.10.045

  164. 164.

    Lo UG, et al. The driver role of JAK-STAT signalling in cancer stemness capabilities leading to new therapeutic strategies for therapy- and castration-resistant prostate cancer. Clin. Transl. Med. 2022;12:e978.

    Not in our library10.1002/ctm2.978

  165. 165.

    Chatterjee D, et al. Cell polarity opposes Jak/STAT-mediated Escargot activation that drives intratumor heterogeneity in a Drosophila tumor model. Cell Rep. 2023;42:112061.

    Not in our library10.1016/j.celrep.2023.112061

  166. 166.
    Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance · 2022
    Corrected
  167. 167.

    Sun L, et al. Modelling liver cancer initiation with organoids derived from directly reprogrammed human hepatocytes. Nat. Cell Biol. 2019;21:1015-1026.

    Not in our library10.1038/s41556-019-0359-5

  168. 168.

    Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31-46.

    Not in our library10.1158/2159-8290.cd-21-1059

  169. 169.

    Baratchian M, et al. H3K9 methylation drives resistance to androgen receptor-antagonist therapy in prostate cancer. Proc. Natl Acad. Sci. USA. 2022;119:e2114324119.

    Not in our library10.1073/pnas.2114324119

  170. 170.

    Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356-361.

    Not in our library10.1038/nature01661

  171. 171.

    Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376:1094-1108.

    Not in our library10.1016/s0140-6736(10)60826-4

  172. 172.

    Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. J. Autoimmun. 2020;110:102400.

    Not in our library10.1016/j.jaut.2019.102400

  173. 173.

    McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 2011;365:2205-2219.

    Not in our library10.1056/nejmra1004965

  174. 174.

    Noack M, Miossec P. Selected cytokine pathways in rheumatoid arthritis. Semin. Immunopathol. 2017;39:365-383.

    Not in our library10.1007/s00281-017-0619-z

  175. 175.

    Pieringer H, Studnicka-Benke A. What is causing my arthritis, doctor? A glimpse beyond the usual suspects in the pathogenesis of rheumatoid arthritis. QJM. 2013;106:219-228.

    Not in our library10.1093/qjmed/hcs205

  176. 176.

    Lubberts E. The IL-23-IL-17 axis in inflammatory arthritis. Nat. Rev. Rheumatol. 2015;11:415-429.

    Not in our library10.1038/nrrheum.2015.53

  177. 177.

    Genovese MC, et al. Effect of filgotinib vs placebo on clinical response in patients with moderate to severe rheumatoid arthritis refractory to disease-modifying antirheumatic drug therapy: the FINCH 2 randomized clinical trial. Jama. 2019;322:315-325.

    Not in our library10.1001/jama.2019.9055

  178. 178.

    Kavanaugh A, et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann. Rheum. Dis. 2017;76:1009-1019.

    Not in our library10.1136/annrheumdis-2016-210105

  179. 179.

    Combe B, et al. Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial. Ann. Rheum. Dis. 2021;80:848-858.

    Not in our library10.1136/annrheumdis-2020-219214

  180. 180.

    Nguyen HN, et al. Autocrine loop involving IL-6 family member LIF, LIF Receptor, and STAT4 drives sustained fibroblast production of inflammatory mediators. Immunity. 2017;46:220-232.

    Not in our library10.1016/j.immuni.2017.01.004

  181. 181.

    Mori T, et al. IL-1β and TNFα-initiated IL-6-STAT3 pathway is critical in mediating inflammatory cytokines and RANKL expression in inflammatory arthritis. Int. Immunol. 2011;23:701-712.

    Not in our library10.1093/intimm/dxr077

  182. 182.

    Kasperkovitz PV, et al. Activation of the STAT1 pathway in rheumatoid arthritis. Ann. Rheum. Dis. 2004;63:233-239.

    Not in our library10.1136/ard.2003.013276

  183. 183.

    van der Pouw Kraan TC, et al. Rheumatoid arthritis is a heterogeneous disease: evidence for differences in the activation of the STAT-1 pathway between rheumatoid tissues. Arthritis Rheum. 2003;48:2132-2145.

    Not in our library10.1002/art.11096

  184. 184.

    Walker JG, et al. Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis. Ann. Rheum. Dis. 2006;65:149-156.

    Not in our library10.1136/ard.2005.037929

  185. 185.

    Tanaka Y, et al. Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to conventional DMARDs: a randomised, double-blind, placebo-controlled phase III trial (RAJ3). Ann. Rheum. Dis. 2019;78:1320-1332.

    Not in our library10.1136/annrheumdis-2019-215163

  186. 186.

    Takeuchi T, et al. Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase III randomised, double-blind, placebo-controlled trial (RAJ4) in Japan. Ann. Rheum. Dis. 2019;78:1305-1319.

    Not in our library10.1136/annrheumdis-2019-215164

  187. 187.

    Takeuchi T, et al. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomised, double-blind, placebo-controlled phase IIb study. Ann. Rheum. Dis. 2016;75:1057-1064.

    Not in our library10.1136/annrheumdis-2015-208279

  188. 188.

    Genovese MC, et al. Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease-modifying antirheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis. Arthritis Rheumatol. 2017;69:932-942.

    Not in our library10.1002/art.40054

  189. 189.

    van der Pouw Kraan TC, et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann. Rheum. Dis. 2007;66:1008-1014.

    Not in our library10.1136/ard.2006.063412

  190. 190.

    Higgs BW, et al. Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann. Rheum. Dis. 2011;70:2029-2036.

    Not in our library10.1136/ard.2011.150326

  191. 191.

    Wang J, Zhao Q. LncRNA LINC-PINT increases SOCS1 expression by sponging miR-155-5p to inhibit the activation of ERK signaling pathway in rheumatoid arthritis synovial fibroblasts induced by TNF-α. Int. Immunopharmacol. 2020;84:106497.

    Not in our library10.1016/j.intimp.2020.106497

  192. 192.

    Kivitz AJ, et al. Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in patients with an inadequate response to methotrexate. Arthritis Rheumatol. 2017;69:709-719.

    Not in our library10.1002/art.39955

  193. 193.

    Papp K, et al. A phase 2a randomized, double-blind, placebo-controlled, sequential dose-escalation study to evaluate the efficacy and safety of ASP015K, a novel Janus kinase inhibitor, in patients with moderate-to-severe psoriasis. Br. J. Dermatol. 2015;173:767-776.

    Not in our library10.1111/bjd.13745

  194. 194.

    Sands BE, et al. Peficitinib, an oral janus kinase inhibitor, in moderate-to-severe ulcerative colitis: results from a randomised, phase 2 study. J. Crohns Colitis. 2018;12:1158-1169.

    Not in our library10.1093/ecco-jcc/jjy085

  195. 195.

    Lauper K, et al. Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the ‘JAK-pot’ collaboration. Ann. Rheum. Dis. 2022;81:1358-1366.

    Not in our library10.1136/annrheumdis-2022-222586

  196. 196.

    Westhovens R, et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1). Ann. Rheum. Dis. 2017;76:998-1008.

    Not in our library10.1136/annrheumdis-2016-210104

  197. 197.

    Vanhoutte F, et al. Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective JAK-1 inhibitor, after short-term treatment of rheumatoid arthritis: results of two randomized phase IIa trials. Arthritis Rheumatol. 2017;69:1949-1959.

    Not in our library10.1002/art.40186

  198. 198.

    Westhovens R, et al. Filgotinib in combination with methotrexate or as monotherapy versus methotrexate monotherapy in patients with active rheumatoid arthritis and limited or no prior exposure to methotrexate: the phase 3, randomised controlled FINCH 3 trial. Ann. Rheum. Dis. 2021;80:727-738.

    Not in our library10.1136/annrheumdis-2020-219213

  199. 199.

    Chen C, et al. A highly selective JAK3 inhibitor is developed for treating rheumatoid arthritis by suppressing γc cytokine-related JAK-STAT signal. Sci. Adv. 2022;8:eabo4363.

    Not in our library10.1126/sciadv.abo4363

  200. 200.

    Charles-Schoeman C, et al. Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs. Ann. Rheum. Dis. 2016;75:1293-1301.

    Not in our library10.1136/annrheumdis-2014-207178

  201. 201.

    Fleischmann R, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012;64:617-629.

    Not in our library10.1002/art.33383

  202. 202.

    van Vollenhoven RF, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N. Engl. J. Med. 2012;367:508-519.

    Not in our library10.1056/nejmoa1112072

  203. 203.

    Kremer J, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann. Intern. Med. 2013;159:253-261.

    Not in our library10.7326/0003-4819-159-4-201308200-00006

  204. 204.

    van der Heijde D, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65:559-570.

    Not in our library10.1002/art.37816

  205. 205.

    Lee EB, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N. Engl. J. Med. 2014;370:2377-2386.

    Not in our library10.1056/nejmoa1310476

  206. 206.

    Mesa RA, et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in janus kinase inhibitor-naïve patients with myelofibrosis. J. Clin. Oncol. 2017;35:3844-3850.

    Not in our library10.1200/jco.2017.73.4418

  207. 207.

    Mesa R, et al. Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Leukemia. 2022;36:2261-2268.

    Not in our library10.1038/s41375-022-01637-7

  208. 208.

    Meyer SC, et al. CHZ868, a type II JAK2 inhibitor, reverses type I JAK inhibitor persistence and demonstrates efficacy in myeloproliferative neoplasms. Cancer Cell. 2015;28:15-28.

    Not in our library10.1016/j.ccell.2015.06.006

  209. 209.

    Harrison CN, et al. Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. Lancet Haematol. 2018;5:e73-e81.

    Not in our library10.1016/s2352-3026(17)30237-5

  210. 210.

    Tefferi A, Vardiman JW. Myelodysplastic syndromes. N. Engl. J. Med. 2009;361:1872-1885.

    Not in our library10.1056/nejmra0902908

  211. 211.

    Zeidan AM, Shallis RM, Wang R, Davidoff A, Ma X. Epidemiology of myelodysplastic syndromes: why characterizing the beast is a prerequisite to taming it. Blood Rev. 2019;34:1-15.

    Not in our library10.1016/j.blre.2018.09.001

  212. 212.

    Aul C, Bowen DT, Yoshida Y. Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica. 1998;83:71-86.

    Not in our library

  213. 213.

    Cazzola M. Myelodysplastic syndromes. N. Engl. J. Med. 2020;383:1358-1374.

    Not in our library10.1056/nejmra1904794

  214. 214.

    Bejar R, et al. Clinical effect of point mutations in myelodysplastic syndromes. N. Engl. J. Med. 2011;364:2496-2506.

    Not in our library10.1056/nejmoa1013343

  215. 215.

    Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia. 2010;24:1128-1138.

    Not in our library10.1038/leu.2010.69

  216. 216.

    Quentmeier H, et al. SOCS2: inhibitor of JAK2V617F-mediated signal transduction. Leukemia. 2008;22:2169-2175.

    Not in our library10.1038/leu.2008.226

  217. 217.

    Plo I, et al. JAK2 stimulates homologous recombination and genetic instability: potential implication in the heterogeneity of myeloproliferative disorders. Blood. 2008;112:1402-1412.

    Not in our library10.1182/blood-2008-01-134114

  218. 218.

    Dawson MA, et al. JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature. 2009;461:819-822.

    Not in our library10.1038/nature08448

  219. 219.

    Thiele J, et al. The international consensus classification of myeloid neoplasms and acute Leukemias: myeloproliferative neoplasms. Am. J. Hematol. 2023;98:166-179.

    Not in our library10.1002/ajh.26751

  220. 220.

    Chifotides HT, Bose P, Verstovsek S. Momelotinib: an emerging treatment for myelofibrosis patients with anemia. J. Hematol. Oncol. 2022;15:7.

    Not in our library10.1186/s13045-021-01157-4

  221. 221.

    Tefferi A, et al. Momelotinib for myelofibrosis: 12-year survival data and retrospective comparison to ruxolitinib. Am. J. Hematol. 2022;97:E433-e435.

    Not in our library10.1002/ajh.26714

  222. 222.

    Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood. 2014;124:3529-3537.

    Not in our library10.1182/blood-2014-05-577635

  223. 223.

    Rampal R, et al. Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood. 2014;123:e123-e133.

    Not in our library10.1182/blood-2014-02-554634

  224. 224.

    Jones AV, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;106:2162-2168.

    Not in our library10.1182/blood-2005-03-1320

  225. 225.

    Ungureanu D, et al. The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling. Nat. Struct. Mol. Biol. 2011;18:971-976.

    Not in our library10.1038/nsmb.2099

  226. 226.

    Kralovics R, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 2005;352:1779-1790.

    Not in our library10.1056/nejmoa051113

  227. 227.

    Woods B, et al. Activation of JAK/STAT signaling in megakaryocytes sustains myeloproliferation in vivo. Clin. Cancer Res. 2019;25:5901-5912.

    Not in our library10.1158/1078-0432.ccr-18-4089

  228. 228.

    Arber DA, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391-2405.

    Not in our library10.1182/blood-2016-03-643544

  229. 229.

    Kollmann K, et al. A novel signalling screen demonstrates that CALR mutations activate essential MAPK signalling and facilitate megakaryocyte differentiation. Leukemia. 2017;31:934-944.

    Not in our library10.1038/leu.2016.280

  230. 230.

    Tefferi A, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014;28:1472-1477.

    Not in our library10.1038/leu.2014.3

  231. 231.
    MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia · 2006
    No notice
  232. 232.

    Nangalia J, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N. Engl. J. Med. 2013;369:2391-2405.

    Not in our library10.1056/nejmoa1312542

  233. 233.

    Klampfl T, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N. Engl. J. Med. 2013;369:2379-2390.

    Not in our library10.1056/nejmoa1311347

  234. 234.

    Elf S, et al. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov. 2016;6:368-381.

    Not in our library10.1158/2159-8290.cd-15-1434

  235. 235.

    Mullally A, Lane SW, Brumme K, Ebert BL. Myeloproliferative neoplasm animal models. Hematol. Oncol. Clin. North Am. 2012;26:1065-1081.

    Not in our library10.1016/j.hoc.2012.07.007

  236. 236.

    Debili N, et al. The Mpl-ligand or thrombopoietin or megakaryocyte growth and differentiative factor has both direct proliferative and differentiative activities on human megakaryocyte progenitors. Blood. 1995;86:2516-2525.

    Not in our library10.1182/blood.v86.7.2516.2516

  237. 237.

    Kaushansky K, et al. Thrombopoietin, the Mp1 ligand, is essential for full megakaryocyte development. Proc. Natl Acad. Sci. USA. 1995;92:3234-3238.

    Not in our library10.1073/pnas.92.8.3234

  238. 238.

    Ku H, Yonemura Y, Kaushansky K, Ogawa M. Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel factor and other early acting cytokines in supporting proliferation of primitive hematopoietic progenitors of mice. Blood. 1996;87:4544-4551.

    Not in our library10.1182/blood.v87.11.4544.bloodjournal87114544

  239. 239.

    Lussana F, et al. Driver mutations (JAK2V617F, MPLW515L/K or CALR), pentraxin-3 and C-reactive protein in essential thrombocythemia and polycythemia vera. J. Hematol. Oncol. 2017;10:54.

    Not in our library10.1186/s13045-017-0425-z

  240. 240.

    Lasho TL, et al. Concurrent MPL515 and JAK2V617F mutations in myelofibrosis: chronology of clonal emergence and changes in mutant allele burden over time. Br. J. Haematol. 2006;135:683-687.

    Not in our library10.1111/j.1365-2141.2006.06348.x

  241. 241.

    Pardanani AD, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006;108:3472-3476.

    Not in our library10.1182/blood-2006-04-018879

  242. 242.

    Langan SM, Irvine AD, Weidinger S. Atopic dermatitis. Lancet. 2020;396:345-360.

    Not in our library10.1016/s0140-6736(20)31286-1

  243. 243.

    Eckert L, et al. The burden of atopic dermatitis in US adults: health care resource utilization data from the 2013 National Health and Wellness Survey. J. Am. Acad. Dermatol. 2018;78:54-61.e51.

    Not in our library10.1016/j.jaad.2017.08.002

  244. 244.

    Drucker AM, Wang AR, Qureshi AA. Research gaps in quality of life and economic burden of atopic dermatitis: the national eczema association burden of disease audit. JAMA Dermatol. 2016;152:873-874.

    Not in our library10.1001/jamadermatol.2016.1978

  245. 245.

    Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J. Am. Acad. Dermatol. 2014;70:338-351.

    Not in our library10.1016/j.jaad.2013.10.010

  246. 246.

    Freitas E, Gooderham M, Torres T. New topical therapies in development for atopic dermatitis. Drugs. 2022;82:843-853.

    Not in our library10.1007/s40265-022-01722-2

  247. 247.

    Tsoi LC, et al. Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses. J. Allergy Clin. Immunol. 2020;145:1406-1415.

    Not in our library10.1016/j.jaci.2019.11.047

  248. 248.
    JAK–STAT signaling pathway in the pathogenesis of atopic dermatitis: An updated review · 2022
    No notice
  249. 249.

    Makowska, K. et al. Immunopathogenesis of atopic dermatitis: focus on interleukins as disease drivers and therapeutic targets for novel treatments. Int. J. Mol. Sci. 24, 781 (2023).

    Not in our library10.3390/ijms24010781

  250. 250.

    Cotter DG, Schairer D, Eichenfield L. Emerging therapies for atopic dermatitis: JAK inhibitors. J. Am. Acad. Dermatol. 2018;78:S53-s62.

    Not in our library10.1016/j.jaad.2017.12.019

  251. 251.

    Nakashima C, Yanagihara S, Otsuka A. Innovation in the treatment of atopic dermatitis: emerging topical and oral Janus kinase inhibitors. Allergol. Int. 2022;71:40-46.

    Not in our library10.1016/j.alit.2021.10.004

  252. 252.

    Kopalli SR, Annamneedi VP, Koppula S. Potential natural biomolecules targeting JAK/STAT/SOCS signaling in the management of atopic dermatitis. Molecules. 2022;27:4660.

    Not in our library10.3390/molecules27144660

  253. 253.

    Klaeschen AS, et al. JAK1/2 inhibition impairs the development and function of inflammatory dendritic epidermal cells in atopic dermatitis. J. Allergy Clin. Immunol. 2021;147:2202-2212.e2208.

    Not in our library10.1016/j.jaci.2020.11.041

  254. 254.

    Reich K, et al. Efficacy and safety of baricitinib combined with topical corticosteroids for treatment of moderate to severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020;156:1333-1343.

    Not in our library10.1001/jamadermatol.2020.3260

  255. 255.

    Simpson EL, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase III trials. Br. J. Dermatol. 2020;183:242-255.

    Not in our library10.1111/bjd.18898

  256. 256.

    Papp K, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: results from 2 phase 3, randomized, double-blind studies. J. Am. Acad. Dermatol. 2021;85:863-872.

    Not in our library10.1016/j.jaad.2021.04.085

  257. 257.

    Papp, K. et al. Long-term safety and disease control with ruxolitinib cream in atopic dermatitis: results from two phase 3 studies. J. Am. Acad. Dermatol.88, 1008–1016 (2022).

    Not in our library10.1016/j.jaad.2022.09.060

  258. 258.

    Kim BS, et al. Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J. Allergy Clin. Immunol. 2020;145:572-582.

    Not in our library10.1016/j.jaci.2019.08.042

  259. 259.

    Reich K, et al. Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2021;397:2169-2181.

    Not in our library10.1016/s0140-6736(21)00589-4

  260. 260.

    Rubbert-Roth A, et al. Trial of upadacitinib or abatacept in rheumatoid arthritis. N. Engl. J. Med. 2020;383:1511-1521.

    Not in our library10.1056/nejmoa2008250

  261. 261.

    Cohen SB, et al. Safety profile of upadacitinib in rheumatoid arthritis: integrated analysis from the SELECT phase III clinical programme. Ann. Rheum. Dis. 2021;80:304-311.

    Not in our library10.1136/annrheumdis-2020-218510

  262. 262.

    Fleischmann RM, et al. Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response. Ann. Rheum. Dis. 2019;78:1454-1462.

    Not in our library10.1136/annrheumdis-2019-215764

  263. 263.

    Mendes-Bastos P, et al. Characterization of acne associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis: A post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials. J. Am. Acad. Dermatol. 2022;87:784-791.

    Not in our library10.1016/j.jaad.2022.06.012

  264. 264.

    Deodhar A, et al. Safety and efficacy of upadacitinib in patients with active ankylosing spondylitis and an inadequate response to nonsteroidal antiinflammatory drug therapy: one-year results of a double-blind, placebo-controlled study and open-label extension. Arthritis Rheumatol. 2022;74:70-80.

    Not in our library10.1002/art.41911

  265. 265.

    van Vollenhoven R, et al. Efficacy and safety of upadacitinib monotherapy in methotrexate-naive patients with moderately-to-severely active rheumatoid arthritis (SELECT-EARLY): a multicenter, multi-country, randomized, double-blind, active comparator-controlled trial. Arthritis Rheumatol. 2020;72:1607-1620.

    Not in our library10.1002/art.41384

  266. 266.

    Fleischmann R, et al. Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a phase iii, double-blind, randomized controlled trial. Arthritis Rheumatol. 2019;71:1788-1800.

    Not in our library10.1002/art.41032

  267. 267.

    Silverberg JI, et al. Upadacitinib plus topical corticosteroids in atopic dermatitis: week 52 AD Up study results. J. Allergy Clin. Immunol. 2022;149:977-987.e914.

    Not in our library10.1016/j.jaci.2021.07.036

  268. 268.

    Guttman-Yassky E, et al. Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial. J. Allergy Clin. Immunol. 2020;145:877-884.

    Not in our library10.1016/j.jaci.2019.11.025

  269. 269.

    Forbes GM. In active UC, upadacitinib induced and maintained remission. Ann. Intern. Med. 2022;175:Jc113.

    Not in our library10.7326/j22-0073

  270. 270.

    Sandborn WJ, et al. Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis. Gastroenterology. 2020;158:2139-2149.e2114.

    Not in our library10.1053/j.gastro.2020.02.030

  271. 271.

    Sandborn WJ, et al. Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn’s disease. Gastroenterology. 2020;158:2123-2138.e2128.

    Not in our library10.1053/j.gastro.2020.01.047

  272. 272.

    Mease PJ, et al. Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2. Ann. Rheum. Dis. 2021;80:312-320.

    Not in our library10.1136/annrheumdis-2020-218870

  273. 273.

    He H, Guttman-Yassky E. JAK inhibitors for atopic dermatitis: an update. Am. J. Clin. Dermatol. 2019;20:181-192.

    Not in our library10.1007/s40257-018-0413-2

  274. 274.

    Mohamed MF, et al. Pharmacokinetics, safety and tolerability of ABT-494, a novel selective JAK 1 inhibitor, in healthy volunteers and subjects with rheumatoid arthritis. Clin. Pharmacokinet. 2016;55:1547-1558.

    Not in our library10.1007/s40262-016-0419-y

  275. 275.

    van der Heijde D, et al. Efficacy and safety of upadacitinib for active ankylosing spondylitis refractory to biological therapy: a double-blind, randomised, placebo-controlled phase 3 trial. Ann. Rheum. Dis. 2022;81:1515-1523.

    Not in our library10.1136/ard-2022-222608

  276. 276.

    Fleischmann RM, et al. Switching between Janus kinase inhibitor upadacitinib and adalimumab following insufficient response: efficacy and safety in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2021;80:432-439.

    Not in our library10.1136/annrheumdis-2020-218412

  277. 277.

    McInnes IB, et al. Trial of upadacitinib and adalimumab for psoriatic arthritis. N. Engl. J. Med. 2021;384:1227-1239.

    Not in our library10.1056/nejmoa2022516

  278. 278.

    Ghosh S, et al. Upadacitinib treatment improves symptoms of bowel urgency and abdominal pain, and correlates with quality of life improvements in patients with moderate to severe ulcerative colitis. J. Crohns Colitis. 2021;15:2022-2030.

    Not in our library10.1093/ecco-jcc/jjab099

  279. 279.

    Guttman-Yassky E, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (Measure Up 1 and Measure Up 2): results from two replicate double-blind, randomised controlled phase 3 trials. Lancet. 2021;397:2151-2168.

    Not in our library10.1016/s0140-6736(21)00588-2

  280. 280.

    Vazquez, M. L. et al. Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): a selective JAK1 clinical candidate for the treatment of autoimmune diseases. J. Med. Chem. 61, 1130–1152 (2018).

    Not in our library10.1021/acs.jmedchem.7b01598

  281. 281.

    Mikhaylov, D., Ungar, B., Renert-Yuval, Y. & Guttman-Yassky, E. Oral Janus kinase inhibitors for atopic dermatitis. Ann. Allergy Asthma Immunol.130, 577–592 (2023).

    Not in our library10.1016/j.anai.2023.01.020

  282. 282.

    De, S. K. Abrocitinib: first globally approved selective janus kinase-1 inhibitor for the treatment of atopic dermatitis. Curr. Med. Chem. 30, 10.2174/0929867330666230216123419, E-pub Ahead of Print (2023).

    Not in our library10.2174/0929867330666230216123419

  283. 283.

    Deeks ED, Duggan S. Abrocitinib: first approval. Drugs. 2021;81:2149-2157.

    Not in our library10.1007/s40265-021-01638-3

  284. 284.

    Bieber T, et al. Abrocitinib versus placebo or dupilumab for atopic dermatitis. N. Engl. J. Med. 2021;384:1101-1112.

    Not in our library10.1056/nejmoa2019380

  285. 285.

    Blauvelt A, et al. Abrocitinib induction, randomized withdrawal, and retreatment in patients with moderate-to-severe atopic dermatitis: results from the JAK1 atopic dermatitis efficacy and safety (JADE) REGIMEN phase 3 trial. J. Am. Acad. Dermatol. 2022;86:104-112.

    Not in our library10.1016/j.jaad.2021.05.075

  286. 286.

    Weidinger S, Schreiber S. Abrocitinib for atopic dermatitis: a step forward. Lancet. 2020;396:215-217.

    Not in our library10.1016/s0140-6736(20)31284-8

  287. 287.

    Simpson EL, et al. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2020;396:255-266.

    Not in our library10.1016/s0140-6736(20)30732-7

  288. 288.

    Uppal SK, Chat VS, Kearns DG, Wu JJ. Abrocitinib for atopic dermatitis. Lancet. 2021;397:195-196.

    Not in our library10.1016/s0140-6736(21)00036-2

  289. 289.

    Schmieder GJ, et al. Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study. Br. J. Dermatol. 2018;179:54-62.

    Not in our library10.1111/bjd.16004

  290. 290.

    Villanueva A. Hepatocellular carcinoma. N. Engl. J. Med. 2019;380:1450-1462.

    Not in our library10.1056/nejmra1713263

  291. 291.

    Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021;71:209-249.

    Not in our library10.3322/caac.21660

  292. 292.

    Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J. Clin. Oncol. 2009;27:1485-1491.

    Not in our library10.1200/jco.2008.20.7753

  293. 293.

    Llovet JM, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.

    Not in our library10.1038/s41572-020-00240-3

  294. 294.

    European Association For The Study Of The Liver & European Organisation For Research And Treatment Of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J. Hepatol. 56, 908–943 (2012).

    Not in our library10.1016/j.jhep.2011.12.001

  295. 295.

    Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.

    Not in our library10.1002/hep.20933

  296. 296.

    Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet. 1999;353:1253-1257.

    Not in our library10.1016/s0140-6736(98)09148-x

  297. 297.

    Parikh ND, Pillai A. Recent advances in hepatocellular carcinoma treatment. Clin. Gastroenterol. Hepatol. 2021;19:2020-2024.

    Not in our library10.1016/j.cgh.2021.05.045

  298. 298.

    Caraglia M, et al. Alpha-interferon and its effects on signalling pathways within cells. Curr. Protein Pept. Sci. 2004;5:475-485.

    Not in our library10.2174/1389203043379378

  299. 299.

    Wang YX, et al. Interferon-inducible MX2 is a host restriction factor of hepatitis B virus replication. J. Hepatol. 2020;72:865-876.

    Not in our library10.1016/j.jhep.2019.12.009

  300. 300.

    Han M, et al. Altered expression of interferon-stimulated genes is strongly associated with therapeutic outcomes in hepatitis B virus infection. Antivir. Res. 2017;147:75-85.

    Not in our library10.1016/j.antiviral.2017.10.003

  301. 301.

    Koeberlein B, et al. Hepatitis B virus overexpresses suppressor of cytokine signaling-3 (SOCS3) thereby contributing to severity of inflammation in the liver. Virus Res. 2010;148:51-59.

    Not in our library10.1016/j.virusres.2009.12.003

  302. 302.

    Robek MD, Boyd BS, Wieland SF, Chisari FV. Signal transduction pathways that inhibit hepatitis B virus replication. Proc. Natl Acad. Sci. USA. 2004;101:1743-1747.

    Not in our library10.1073/pnas.0308340100

  303. 303.

    Gao D, et al. Down-regulation of suppressor of cytokine signaling 3 by miR-122 enhances interferon-mediated suppression of hepatitis B virus. Antivir. Res. 2015;118:20-28.

    Not in our library10.1016/j.antiviral.2015.03.001

  304. 304.

    Khan MGM, et al. Prognostic significance of SOCS1 and SOCS3 tumor suppressors and oncogenic signaling pathway genes in hepatocellular carcinoma. BMC Cancer. 2020;20:774.

    Not in our library10.1186/s12885-020-07285-3

  305. 305.

    Li H, et al. C1QTNF1-AS1 regulates the occurrence and development of hepatocellular carcinoma by regulating miR-221-3p/SOCS3. Hepatol. Int. 2019;13:277-292.

    Not in our library10.1007/s12072-019-09944-5

  306. 306.

    Liu ZK, et al. EYA2 suppresses the progression of hepatocellular carcinoma via SOCS3-mediated blockade of JAK/STAT signaling. Mol. Cancer. 2021;20:79.

    Not in our library10.1186/s12943-021-01377-9

  307. 307.

    Zhao Z, et al. CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway. J. Exp. Clin. Cancer Res. 2020;39:259.

    Not in our library10.1186/s13046-020-01769-7

  308. 308.

    Guo H, et al. HHLA2 activates the JAK/STAT signaling pathway by binding to TMIGD2 in hepatocellular carcinoma cells. Inflammation. 2022;45:1585-1599.

    Not in our library10.1007/s10753-022-01644-x

  309. 309.

    Mora LB, et al. Constitutive activation of Stat3 in human prostate tumors and cell lines: direct inhibition of Stat3 signaling induces apoptosis of prostate cancer cells. Cancer Res. 2002;62:6659-6666.

    Not in our library

  310. 310.

    Gao L, et al. Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin. Cancer Res. 2005;11:6333-6341.

    Not in our library10.1158/1078-0432.ccr-05-0148

  311. 311.

    Liu C, et al. Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition. Prostate. 2015;75:1341-1353.

    Not in our library10.1002/pros.23015

  312. 312.

    Liu C, et al. Inhibition of constitutively active Stat3 reverses enzalutamide resistance in LNCaP derivative prostate cancer cells. Prostate. 2014;74:201-209.

    Not in our library10.1002/pros.22741

  313. 313.

    Onkar SS, et al. The Great Immune Escape: Understanding the Divergent Immune Response in Breast Cancer Subtypes. Cancer Discov. 2023;13:23-40.

    Not in our library10.1158/2159-8290.cd-22-0475

  314. 314.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J. Clin. 2019;69:7-34.

    Not in our library10.3322/caac.21551

  315. 315.

    Feng R, et al. Cancer situation in China: what does the China cancer map indicate from the first national death survey to the latest cancer registration? Cancer Commun. (Lond.). 2023;43:75-86.

    Not in our library10.1002/cac2.12393

  316. 316.

    Luen, S. J. et al. Genomic characterisation of hormone receptor-positive breast cancer arising in very young women. Ann Oncol, (2023).

    Not in our library10.1016/j.annonc.2023.01.009

  317. 317.

    Chlebowski RT, et al. Ethnicity and breast cancer: factors influencing differences in incidence and outcome. J. Natl Cancer Inst. 2005;97:439-448.

    Not in our library10.1093/jnci/dji064

  318. 318.

    Wong GL, Manore SG, Doheny DL, Lo HW. STAT family of transcription factors in breast cancer: Pathogenesis and therapeutic opportunities and challenges. Semin. Cancer Biol. 2022;86:84-106.

    Not in our library10.1016/j.semcancer.2022.08.003

  319. 319.
    Targeting STAT3 in Cancer Immunotherapy · 2020
    No notice
  320. 320.

    Bromberg J. Signal transducers and activators of transcription as regulators of growth, apoptosis and breast development. Breast Cancer Res. 2000;2:86-90.

    Not in our library10.1186/bcr38

  321. 321.

    Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat. Rev. Cancer. 2014;14:736-746.

    Not in our library10.1038/nrc3818

  322. 322.

    Johnson DE, O’Keefe RA, Grandis JR. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 2018;15:234-248.

    Not in our library10.1038/nrclinonc.2018.8

  323. 323.

    Wang T, et al. JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 2018;27:136-150.e135.

    Not in our library10.1016/j.cmet.2017.11.001

  324. 324.

    Li J, et al. Tumor cell-intrinsic CD96 mediates chemoresistance and cancer stemness by regulating mitochondrial fatty acid β-oxidation. Adv. Sci. (Weinh.). 2023;10:e2202956.

    Not in our library10.1002/advs.202202956

  325. 325.

    Zhu Y, et al. Natural product preferentially targets redox and metabolic adaptations and aberrantly active STAT3 to inhibit breast tumor growth in vivo. Cell Death Dis. 2022;13:1022.

    Not in our library10.1038/s41419-022-05477-2

  326. 326.

    Liu C, et al. A highly potent small-molecule antagonist of exportin-1 selectively eliminates CD44(+)CD24(-) enriched breast cancer stem-like cells. Drug Resist. Updat. 2023;66:100903.

    Not in our library10.1016/j.drup.2022.100903

  327. 327.

    Meraviglia-Crivelli D, et al. IL-6/STAT3 signaling in tumor cells restricts the expression of frameshift-derived neoantigens by SMG1 induction. Mol. Cancer. 2022;21:211.

    Not in our library10.1186/s12943-022-01679-6

  328. 328.

    Dinakar YH, et al. Role of STAT3 in the initiation, progression, proliferation and metastasis of breast cancer and strategies to deliver JAK and STAT3 inhibitors. Life Sci. 2022;309:120996.

    Not in our library10.1016/j.lfs.2022.120996

  329. 329.

    DeMichele A, et al. Host genetic variants in the interleukin-6 promoter predict poor outcome in patients with estrogen receptor-positive, node-positive breast cancer. Cancer Res. 2009;69:4184-4191.

    Not in our library10.1158/0008-5472.can-08-2989

  330. 330.

    Dethlefsen C, Højfeldt G, Hojman P. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res. Treat. 2013;138:657-664.

    Not in our library10.1007/s10549-013-2488-z

  331. 331.

    Rodriguez-Barrueco R, et al. Inhibition of the autocrine IL-6-JAK2-STAT3-calprotectin axis as targeted therapy for HR-/HER2+ breast cancers. Genes Dev. 2015;29:1631-1648.

    Not in our library10.1101/gad.262642.115

  332. 332.

    Bottos A, et al. Decreased NK-cell tumour immunosurveillance consequent to JAK inhibition enhances metastasis in breast cancer models. Nat. Commun. 2016;7:12258.

    Not in our library10.1038/ncomms12258

  333. 333.

    Irey EA, et al. JAK/STAT inhibition in macrophages promotes therapeutic resistance by inducing expression of protumorigenic factors. Proc. Natl Acad. Sci. USA. 2019;116:12442-12451.

    Not in our library10.1073/pnas.1816410116

  334. 334.

    Tao J, et al. JAK-STAT signaling is activated in the kidney and peripheral blood cells of patients with focal segmental glomerulosclerosis. Kidney Int. 2018;94:795-808.

    Not in our library10.1016/j.kint.2018.05.022

  335. 335.

    Pang M, et al. A novel STAT3 inhibitor, S3I-201, attenuates renal interstitial fibroblast activation and interstitial fibrosis in obstructive nephropathy. Kidney Int. 2010;78:257-268.

    Not in our library10.1038/ki.2010.154

  336. 336.

    Koike K, et al. Protective role of JAK/STAT signaling against renal fibrosis in mice with unilateral ureteral obstruction. Clin. Immunol. 2014;150:78-87.

    Not in our library10.1016/j.clim.2013.11.003

  337. 337.

    Luan J, et al. miR-150-based RNA interference attenuates tubulointerstitial fibrosis through the SOCS1/JAK/STAT pathway in vivo and in vitro. Mol. Ther. Nucleic Acids. 2020;22:871-884.

    Not in our library10.1016/j.omtn.2020.10.008

  338. 338.

    Tao J, et al. JAK-STAT activity in peripheral blood cells and kidney tissue in IgA nephropathy. Clin. J. Am. Soc. Nephrol. 2020;15:973-982.

    Not in our library10.2215/cjn.11010919

  339. 339.

    Wang X, Shaw S, Amiri F, Eaton DC, Marrero MB. Inhibition of the Jak/STAT signaling pathway prevents the high glucose-induced increase in tgf-beta and fibronectin synthesis in mesangial cells. Diabetes. 2002;51:3505-3509.

    Not in our library10.2337/diabetes.51.12.3505

  340. 340.

    Marrero MB, Banes-Berceli AK, Stern DM, Eaton DC. Role of the JAK/STAT signaling pathway in diabetic nephropathy. Am. J. Physiol. Ren. Physiol. 2006;290:F762-F768.

    Not in our library10.1152/ajprenal.00181.2005

  341. 341.

    Sengupta U, Ukil S, Dimitrova N, Agrawal S. Expression-based network biology identifies alteration in key regulatory pathways of type 2 diabetes and associated risk/complications. PLoS One. 2009;4:e8100.

    Not in our library10.1371/journal.pone.0008100

  342. 342.

    Chen D, et al. JAK/STAT pathway promotes the progression of diabetic kidney disease via autophagy in podocytes. Eur. J. Pharm. 2021;902:174121.

    Not in our library10.1016/j.ejphar.2021.174121

  343. 343.

    Zhang H, et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int. 2017;92:909-921.

    Not in our library10.1016/j.kint.2017.03.027

  344. 344.

    Casarella A, et al. Autosomic dominant polycystic kidney disease and metformin: old knowledge and new insights on retarding progression of chronic kidney disease. Med. Res. Rev. 2022;42:629-640.

    Not in our library10.1002/med.21850

  345. 345.

    Fragiadaki M, et al. STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease. Kidney Int. 2017;91:575-586.

    Not in our library10.1016/j.kint.2016.10.039

  346. 346.

    Patera F, Cudzich-Madry A, Huang Z, Fragiadaki M. Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis. Sci. Rep. 2019;9:4491.

    Not in our library10.1038/s41598-019-41106-3

  347. 347.

    Arakawa T, et al. Activation of signal transducer and activator of transcription 3 correlates with cell proliferation and renal injury in human glomerulonephritis. Nephrol. Dial. Transpl. 2008;23:3418-3426.

    Not in our library10.1093/ndt/gfn314

  348. 348.

    Borie DC, et al. Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates. Transplantation. 2005;80:1756-1764.

    Not in our library10.1097/01.tp.0000184634.25042.ea

  349. 349.

    Borie DC, et al. Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation. 2005;79:791-801.

    Not in our library10.1097/01.tp.0000157117.30290.6f

  350. 350.

    Changelian PS, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science. 2003;302:875-878.

    Not in our library10.1126/science.1087061

  351. 351.

    Adachi Y, et al. Inhibition of FGFR reactivates IFNγ signaling in tumor cells to enhance the combined antitumor activity of lenvatinib with anti-PD-1 antibodies. Cancer Res. 2022;82:292-306.

    Not in our library10.1158/0008-5472.can-20-2426

  352. 352.

    Favoino E, et al. Working and safety profiles of JAK/STAT signaling inhibitors. Are these small molecules also smart? Autoimmun. Rev. 2021;20:102750.

    Not in our library10.1016/j.autrev.2021.102750

  353. 353.

    Podewski EK, et al. Alterations in Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling in patients with end-stage dilated cardiomyopathy. Circulation. 2003;107:798-802.

    Not in our library10.1161/01.cir.0000057545.82749.ff

  354. 354.

    Panés J, Vermeire S. JAK inhibitors: back to small molecules for the treatment of IBD. J. Crohns Colitis. 2020;14:S711-s712.

    Not in our library10.1093/ecco-jcc/jjaa109

  355. 355.

    Miyagi T, et al. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J. Exp. Med. 2007;204:2383-2396.

    Not in our library10.1084/jem.20070401

  356. 356.

    Thieu VT, et al. Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. Immunity. 2008;29:679-690.

    Not in our library10.1016/j.immuni.2008.08.017

  357. 357.

    Weinstein JS, et al. STAT4 and T-bet control follicular helper T cell development in viral infections. J. Exp. Med. 2018;215:337-355.

    Not in our library10.1084/jem.20170457

  358. 358.

    Guenterberg KD, et al. Interleukin-29 binds to melanoma cells inducing Jak-STAT signal transduction and apoptosis. Mol. Cancer Ther. 2010;9:510-520.

    Not in our library10.1158/1535-7163.mct-09-0461

  359. 359.

    Kroon P, et al. JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. Cancer Res. 2013;73:5288-5298.

    Not in our library10.1158/0008-5472.can-13-0874

  360. 360.

    Tanaka T, Narazaki M, Ogata A, Kishimoto T. A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy. Semin. Immunol. 2014;26:88-96.

    Not in our library10.1016/j.smim.2014.01.009

  361. 361.

    Chen LYC, et al. Soluble interleukin-6 receptor in the COVID-19 cytokine storm syndrome. Cell Rep. Med. 2021;2:100269.

    Not in our library10.1016/j.xcrm.2021.100269

  362. 362.

    Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK. Biochemical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis. Immunity. 1998;8:615-623.

    Not in our library10.1016/s1074-7613(00)80566-x

  363. 363.

    Liu X, et al. Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev. 1997;11:179-186.

    Not in our library10.1101/gad.11.2.179

  364. 364.

    Lin JX, Leonard WJ. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene. 2000;19:2566-2576.

    Not in our library10.1038/sj.onc.1203523

  365. 365.

    Mui AL, Wakao H, O’Farrell AM, Harada N, Miyajima A. Interleukin-3, granulocyte-macrophage colony stimulating factor and interleukin-5 transduce signals through two STAT5 homologs. EMBO J. 1995;14:1166-1175.

    Not in our library10.1002/j.1460-2075.1995.tb07100.x

  366. 366.

    Wakao H, Gouilleux F, Groner B. Mammary gland factor (MGF) is a novel member of the cytokine regulated transcription factor gene family and confers the prolactin response. EMBO J. 1995;14:854-855.

    Not in our library10.1002/j.1460-2075.1995.tb07064.x

  367. 367.

    Azam M, et al. Interleukin-3 signals through multiple isoforms of Stat5. EMBO J. 1995;14:1402-1411.

    Not in our library10.1002/j.1460-2075.1995.tb07126.x

  368. 368.

    Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin. Cancer Res. 2002;8:945-954.

    Not in our library

  369. 369.

    Page BD, et al. Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity. J. Med Chem. 2012;55:1047-1055.

    Not in our library10.1021/jm200720n

  370. 370.

    Lis C, et al. Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells. Sci. Rep. 2017;7:17390.

    Not in our library10.1038/s41598-017-17600-x

  371. 371.

    Caldenhoven E, et al. STAT3beta, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription. J. Biol. Chem. 1996;271:13221-13227.

    Not in our library10.1074/jbc.271.22.13221

  372. 372.

    Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol. 2007;7:41-51.

    Not in our library10.1038/nri1995

  373. 373.

    Hillmer EJ, Zhang H, Li HS, Watowich SS. STAT3 signaling in immunity. Cytokine Growth Factor Rev. 2016;31:1-15.

    Not in our library10.1016/j.cytogfr.2016.05.001

  374. 374.

    Xiao, L. et al. IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity. J. Clin. Invest. 132, e153247 (2022).

    Not in our library10.1172/jci153247

  375. 375.

    MacDonagh L, et al. BBI608 inhibits cancer stemness and reverses cisplatin resistance in NSCLC. Cancer Lett. 2018;428:117-126.

    Not in our library10.1016/j.canlet.2018.04.008

  376. 376.

    Bi S, et al. Napabucasin (BBI608) eliminate AML cells in vitro and in vivo via inhibition of Stat3 pathway and induction of DNA damage. Eur. J. Pharm. 2019;855:252-261.

    Not in our library10.1016/j.ejphar.2019.05.020

  377. 377.

    Bitsch R, et al. STAT3 inhibitor Napabucasin abrogates MDSC immunosuppressive capacity and prolongs survival of melanoma-bearing mice. J. Immunother. Cancer. 2022;10:e004384.

    Not in our library10.1136/jitc-2021-004384

  378. 378.

    Jonker DJ, et al. Napabucasin versus placebo in refractory advanced colorectal cancer: a randomised phase 3 trial. Lancet Gastroenterol. Hepatol. 2018;3:263-270.

    Not in our library10.1016/s2468-1253(18)30009-8

  379. 379.

    Kim MJ, et al. OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells. Cancer Lett. 2013;335:145-152.

    Not in our library10.1016/j.canlet.2013.02.010

  380. 380.

    Brambilla L, Lahiri T, Cammer M, Levy DE. STAT3 inhibitor OPB-51602 is cytotoxic to tumor cells through inhibition of complex I and ROS induction. iScience. 2020;23:101822.

    Not in our library10.1016/j.isci.2020.101822

  381. 381.

    Hirpara J, et al. Metabolic reprogramming of oncogene-addicted cancer cells to OXPHOS as a mechanism of drug resistance. Redox Biol. 2019;25:101076.

    Not in our library10.1016/j.redox.2018.101076

  382. 382.

    Genini D, et al. Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells. Proc. Natl Acad. Sci. USA. 2017;114:E4924-e4933.

    Not in our library10.1073/pnas.1615730114

  383. 383.

    Wong AL, et al. Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies. Ann. Oncol. 2015;26:998-1005.

    Not in our library10.1093/annonc/mdv026

  384. 384.

    Kasembeli MM, et al. TTI-101: a competitive inhibitor of STAT3 that spares oxidative phosphorylation and reverses mechanical allodynia in mouse models of neuropathic pain. Biochem. Pharm. 2021;192:114688.

    Not in our library10.1016/j.bcp.2021.114688

  385. 385.

    Zhao Y, et al. Analysis and validation of human targets and treatments using a hepatocellular carcinoma-immune humanized mouse model. Hepatology. 2021;74:1395-1410.

    Not in our library10.1002/hep.31812

  386. 386.

    Jung KH, et al. Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in mice. Clin. Cancer Res. 2017;23:5537-5546.

    Not in our library10.1158/1078-0432.ccr-16-2253

  387. 387.

    Di JX, Zhang HY. C188-9, a small-molecule STAT3 inhibitor, exerts an antitumor effect on head and neck squamous cell carcinoma. Anticancer Drugs. 2019;30:846-853.

    Not in our library10.1097/cad.0000000000000783

  388. 388.

    Pedroza M, et al. Role of STAT3 in skin fibrosis and transforming growth factor beta signalling. Rheumatology. 2018;57:1838-1850.

    Not in our library10.1093/rheumatology/kex347

  389. 389.

    Robinson P, et al. Genetic and small-molecule modulation of stat3 in a mouse model of Crohn’s disease. J. Clin. Med. 2022;11:7020.

    Not in our library10.3390/jcm11237020

  390. 390.

    Sheng W, et al. STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Res. 2014;24:1387-1402.

    Not in our library10.1038/cr.2014.154

  391. 391.
    Niclosamide, an antihelmintic drug, enhances efficacy of PD-1/PD-L1 immune checkpoint blockade in non-small cell lung cancer · 2019
    Not checked
  392. 392.

    Guha P, et al. STAT3 inhibition induces Bax-dependent apoptosis in liver tumor myeloid-derived suppressor cells. Oncogene. 2019;38:533-548.

    Not in our library10.1038/s41388-018-0449-z

  393. 393.

    Pei J, et al. STAT3 inhibition enhances CDN-induced STING signaling and antitumor immunity. Cancer Lett. 2019;450:110-122.

    Not in our library10.1016/j.canlet.2019.02.029

  394. 394.

    Moreira D, et al. STAT3 inhibition combined with CpG immunostimulation activates antitumor immunity to eradicate genetically distinct castration-resistant prostate cancers. Clin. Cancer Res. 2018;24:5948-5962.

    Not in our library10.1158/1078-0432.ccr-18-1277

  395. 395.

    Jamieson S, Wallace CE, Das N, Bhattacharyya P, Bishayee A. Guava (Psidium guajava L.): a glorious plant with cancer preventive and therapeutic potential. Crit. Rev. Food Sci. Nutr. 2023;63:192-223.

    Not in our library10.1080/10408398.2021.1945531

  396. 396.

    Sun Q, et al. Flavonoids regulate tumor-associated macrophages - from structure-activity relationship to clinical potential (Review). Pharm. Res. 2022;184:106419.

    Not in our library10.1016/j.phrs.2022.106419

  397. 397.

    Kalick LS, et al. Mangosteen for malignancy prevention and intervention: current evidence, molecular mechanisms, and future perspectives. Pharm. Res. 2023;188:106630.

    Not in our library10.1016/j.phrs.2022.106630

  398. 398.

    Yang J, Wang L, Guan X, Qin JJ. Inhibiting STAT3 signaling pathway by natural products for cancer prevention and therapy: In vitro and in vivo activity and mechanisms of action. Pharm. Res. 2022;182:106357.

    Not in our library10.1016/j.phrs.2022.106357

  399. 399.

    Mahata S, et al. In-silico and in-vitro investigation of STAT3-PIM1 heterodimeric complex: Its mechanism and inhibition by curcumin for cancer therapeutics. Int. J. Biol. Macromol. 2022;208:356-366.

    Not in our library10.1016/j.ijbiomac.2022.03.137

  400. 400.

    Patel SS, et al. Cellular and molecular mechanisms of curcumin in prevention and treatment of disease. Crit. Rev. Food Sci. Nutr. 2020;60:887-939.

    Not in our library10.1080/10408398.2018.1552244

  401. 401.

    Tian M, Tian D, Qiao X, Li J, Zhang L. Modulation of Myb-induced NF-kB -STAT3 signaling and resulting cisplatin resistance in ovarian cancer by dietary factors. J. Cell Physiol. 2019;234:21126-21134.

    Not in our library10.1002/jcp.28715

  402. 402.

    Chen YC, et al. Myricetin inhibits interferon-γ-induced PD-L1 and IDO1 expression in lung cancer cells. Biochem. Pharm. 2022;197:114940.

    Not in our library10.1016/j.bcp.2022.114940

  403. 403.

    Liu K, et al. Focus on immune checkpoint PD-1/PD-L1 pathway: new advances of polyphenol phytochemicals in tumor immunotherapy. Biomed. Pharmacother. 2022;154:113618.

    Not in our library10.1016/j.biopha.2022.113618

  404. 404.

    Runtsch MC, et al. Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages. Cell Metab. 2022;34:487-501.e488.

    Not in our library10.1016/j.cmet.2022.02.002

  405. 405.

    Guan X, et al. Dual inhibition of MYC and SLC39A10 by a novel natural product STAT3 inhibitor derived from Chaetomium globosum suppresses tumor growth and metastasis in gastric cancer. Pharm. Res. 2023;189:106703.

    Not in our library10.1016/j.phrs.2023.106703

  406. 406.

    Cianciulli A, Calvello R, Porro C, Trotta T, Panaro MA. Understanding the role of SOCS signaling in neurodegenerative diseases: current and emerging concepts. Cytokine Growth Factor Rev. 2017;37:67-79.

    Not in our library10.1016/j.cytogfr.2017.07.005

  407. 407.
    SOCS1 mimetics and antagonists: a complementary approach to positive and negative regulation of immune function · 2015
    Not checked
  408. 408.

    McLornan DP, Pope JE, Gotlib J, Harrison CN. Current and future status of JAK inhibitors. Lancet. 2021;398:803-816.

    Not in our library10.1016/s0140-6736(21)00438-4

  409. 409.

    Liu C, Kieltyka J, Fleischmann R, Gadina M, O’Shea JJ. A decade of JAK inhibitors: what have we learned and what may be the future? Arthritis Rheumatol. 2021;73:2166-2178.

    Not in our library10.1002/art.41906

  410. 410.

    De Vries LCS, Wildenberg ME, De Jonge WJ, D’Haens GR. The future of janus kinase inhibitors in inflammatory bowel disease. J. Crohns Colitis. 2017;11:885-893.

    Not in our library10.1093/ecco-jcc/jjx003

  411. 411.

    Verstovsek S, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N. Engl. J. Med. 2010;363:1117-1127.

    Not in our library10.1056/nejmoa1002028

  412. 412.

    Rosmarin D, et al. Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. Lancet. 2020;396:110-120.

    Not in our library10.1016/s0140-6736(20)30609-7

  413. 413.

    Zeiser R, et al. Ruxolitinib for glucocorticoid-refractory acute graft-versus-host disease. N. Engl. J. Med. 2020;382:1800-1810.

    Not in our library10.1056/nejmoa1917635

  414. 414.

    Hurwitz HI, et al. Randomized, double-blind, phase ii study of ruxolitinib or placebo in combination with capecitabine in patients with metastatic pancreatic cancer for whom therapy with gemcitabine has failed. J. Clin. Oncol. 2015;33:4039-4047.

    Not in our library10.1200/jco.2015.61.4578

  415. 415.

    Mesa RA, et al. Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. J. Clin. Oncol. 2013;31:1285-1292.

    Not in our library10.1200/jco.2012.44.4489

  416. 416.

    Kiladjian JJ, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7:e226-e237.

    Not in our library10.1016/s2352-3026(19)30207-8

  417. 417.

    Harrison CN, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematol. 2017;4:e317-e324.

    Not in our library10.1016/s2352-3026(17)30088-1

  418. 418.

    Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors: a 2020 update. Pharm. Res. 2020;152:104609.

    Not in our library10.1016/j.phrs.2019.104609

  419. 419.

    Vannucchi AM, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N. Engl. J. Med. 2015;372:426-435.

    Not in our library10.1056/nejmoa1409002

  420. 420.

    Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N. Engl. J. Med. 2012;366:799-807.

    Not in our library10.1056/nejmoa1110557

  421. 421.

    Passamonti F, et al. Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol. 2017;18:88-99.

    Not in our library10.1016/s1470-2045(16)30558-7

  422. 422.

    Harrison CN, et al. Addition of navitoclax to ongoing ruxolitinib therapy for patients with myelofibrosis with progression or suboptimal response: phase ii safety and efficacy. J. Clin. Oncol. 2022;40:1671-1680.

    Not in our library10.1200/jco.21.02188

  423. 423.

    Dao KT, et al. Efficacy of ruxolitinib in patients with chronic neutrophilic leukemia and atypical chronic myeloid leukemia. J. Clin. Oncol. 2020;38:1006-1018.

    Not in our library10.1200/jco.19.00895

  424. 424.

    Harrison C, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N. Engl. J. Med. 2012;366:787-798.

    Not in our library10.1056/nejmoa1110556

  425. 425.

    Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N. Engl. J. Med. 2011;365:1455-1457.

    Not in our library10.1056/nejmc1109555

  426. 426.
    Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis · 2016
    Corrected
  427. 427.

    Kvasnicka HM, et al. Long-term effects of ruxolitinib versus best available therapy on bone marrow fibrosis in patients with myelofibrosis. J. Hematol. Oncol. 2018;11:42.

    Not in our library10.1186/s13045-018-0585-5

  428. 428.

    Zeiser R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N. Engl. J. Med. 2021;385:228-238.

    Not in our library10.1056/nejmoa2033122

  429. 429.

    Rudra S, et al. Ruxolitinib: targeted approach for treatment of autoinflammatory very early onset inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 2022;20:1408-1410.e1402.

    Not in our library10.1016/j.cgh.2021.07.040

  430. 430.

    Bader-Meunier B, et al. Effectiveness and safety of ruxolitinib for the treatment of refractory systemic idiopathic juvenile arthritis like associated with interstitial lung disease: a case report. Ann. Rheum. Dis. 2022;81:e20.

    Not in our library10.1136/annrheumdis-2020-216983

  431. 431.

    Han MK, et al. Ruxolitinib in addition to standard of care for the treatment of patients admitted to hospital with COVID-19 (RUXCOVID): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Rheumatol. 2022;4:e351-e361.

    Not in our library10.1016/s2665-9913(22)00044-3

  432. 432.

    Fisher DAC, et al. Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT, MAP kinase, and NFκB signaling. Leukemia. 2019;33:1978-1995.

    Not in our library10.1038/s41375-019-0379-y

  433. 433.

    Wathes R, Moule S, Milojkovic D. Progressive multifocal leukoencephalopathy associated with ruxolitinib. N. Engl. J. Med. 2013;369:197-198.

    Not in our library10.1056/nejmc1302135

  434. 434.

    Coltro G, et al. A life-threatening ruxolitinib discontinuation syndrome. Am. J. Hematol. 2017;92:833-838.

    Not in our library10.1002/ajh.24775

  435. 435.

    Tvorogov D, et al. Accumulation of JAK activation loop phosphorylation is linked to type I JAK inhibitor withdrawal syndrome in myelofibrosis. Sci. Adv. 2018;4:eaat3834.

    Not in our library10.1126/sciadv.aat3834

  436. 436.

    Houthuys JF, Wilmer AP, Peetermans M, Meersseman P, Devos T. Severe ARDS due to ruxolitinib discontinuation syndrome: case presentation and literature review. Heliyon. 2022;8:e11782.

    Not in our library10.1016/j.heliyon.2022.e11782

  437. 437.

    Jagasia M, et al. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. Blood. 2020;135:1739-1749.

    Not in our library10.1182/blood.2020004823

  438. 438.

    Guglielmelli P, et al. Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. Blood. 2014;123:2157-2160.

    Not in our library10.1182/blood-2013-11-536557

  439. 439.

    Passamonti F, et al. Impact of ruxolitinib on the natural history of primary myelofibrosis: a comparison of the DIPSS and the COMFORT-2 cohorts. Blood. 2014;123:1833-1835.

    Not in our library10.1182/blood-2013-12-544411

  440. 440.
    Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses · 2017
    No notice
  441. 441.
    Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial · 2017
    No notice
  442. 442.

    Marconi VC, et al. Randomized trial of ruxolitinib in antiretroviral-treated adults with human immunodeficiency virus. Clin. Infect. Dis. 2022;74:95-104.

    Not in our library10.1093/cid/ciab212

  443. 443.

    Scott LJ. Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. Drugs. 2013;73:857-874.

    Not in our library10.1007/s40265-013-0065-8

  444. 444.

    Dhillon S. Tofacitinib: a review in rheumatoid arthritis. Drugs. 2017;77:1987-2001.

    Not in our library10.1007/s40265-017-0835-9

  445. 445.

    Guimarães PO, et al. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N. Engl. J. Med. 2021;385:406-415.

    Not in our library10.1056/nejmoa2101643

  446. 446.

    Sandborn WJ, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N. Engl. J. Med. 2017;376:1723-1736.

    Not in our library10.1056/nejmoa1606910

  447. 447.

    Sandborn WJ, et al. Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. N. Engl. J. Med. 2012;367:616-624.

    Not in our library10.1056/nejmoa1112168

  448. 448.

    Ytterberg SR, et al. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N. Engl. J. Med. 2022;386:316-326.

    Not in our library10.1056/nejmoa2109927

  449. 449.

    Wollenhaupt J, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J. Rheumatol. 2014;41:837-852.

    Not in our library10.3899/jrheum.130683

  450. 450.

    Kremer JM, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60:1895-1905.

    Not in our library10.1002/art.24567

  451. 451.

    Sandborn WJ, et al. Efficacy and safety of extended induction with tofacitinib for the treatment of ulcerative colitis. Clin. Gastroenterol. Hepatol. 2022;20:1821-1830.e1823.

    Not in our library10.1016/j.cgh.2020.10.038

  452. 452.

    Sandborn WJ, et al. Efficacy and safety of tofacitinib in ulcerative colitis based on prior tumor necrosis factor inhibitor failure status. Clin. Gastroenterol. Hepatol. 2022;20:591-601.e598.

    Not in our library10.1016/j.cgh.2021.02.043

  453. 453.

    Sandborn WJ, et al. Safety of tofacitinib for treatment of ulcerative colitis, based on 4.4 years of data from global clinical trials. Clin. Gastroenterol. Hepatol. 2019;17:1541-1550.

    Not in our library10.1016/j.cgh.2018.11.035

  454. 454.

    Gladman D, et al. Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N. Engl. J. Med. 2017;377:1525-1536.

    Not in our library10.1056/nejmoa1615977

  455. 455.

    Khosrow-Khavar F, Kim SC, Lee H, Lee SB, Desai RJ. Tofacitinib and risk of cardiovascular outcomes: results from the safety of TofAcitinib in routine care patients with Rheumatoid Arthritis (STAR-RA) study. Ann. Rheum. Dis. 2022;81:798-804.

    Not in our library10.1136/annrheumdis-2021-221915

  456. 456.

    Deodhar A, et al. Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study. Ann. Rheum. Dis. 2021;80:1004-1013.

    Not in our library10.1136/annrheumdis-2020-219601

  457. 457.

    Krueger J, et al. Tofacitinib attenuates pathologic immune pathways in patients with psoriasis: a randomized phase 2 study. J. Allergy Clin. Immunol. 2016;137:1079-1090.

    Not in our library10.1016/j.jaci.2015.12.1318

  458. 458.

    Sandborn WJ, et al. A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn’s disease. Clin. Gastroenterol. Hepatol. 2014;12:1485-1493.e1482.

    Not in our library10.1016/j.cgh.2014.01.029

  459. 459.

    Bissonnette R, et al. Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial. Br. J. Dermatol. 2016;175:902-911.

    Not in our library10.1111/bjd.14871

  460. 460.

    Ma C, et al. Innovations in oral therapies for inflammatory bowel disease. Drugs. 2019;79:1321-1335.

    Not in our library10.1007/s40265-019-01169-y

  461. 461.

    Colombel JF, et al. Maintenance of remission with tofacitinib therapy in patients with ulcerative colitis. Clin. Gastroenterol. Hepatol. 2022;20:116-125.e115.

    Not in our library10.1016/j.cgh.2020.10.004

  462. 462.

    Kotwani P, Terdiman J, Lewin S. Tofacitinib for rescue therapy in acute severe ulcerative colitis: a real-world experience. J. Crohns Colitis. 2020;14:1026-1028.

    Not in our library10.1093/ecco-jcc/jjaa018

  463. 463.

    Takeuchi T. Cytokines and cytokine receptors as targets of immune-mediated inflammatory diseases-RA as a role model. Inflamm. Regen. 2022;42:35.

    Not in our library10.1186/s41232-022-00221-x

  464. 464.

    Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann. Rheum. Dis. 82, 3–18 (2022).

    Not in our library10.1136/ard-2022-223356

  465. 465.

    Fleischmann R, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 2012;367:495-507.

    Not in our library10.1056/nejmoa1109071

  466. 466.

    Mease P, et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N. Engl. J. Med. 2017;377:1537-1550.

    Not in our library10.1056/nejmoa1615975

  467. 467.

    Panés J, et al. Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two phase IIb randomised placebo-controlled trials. Gut. 2017;66:1049-1059.

    Not in our library10.1136/gutjnl-2016-312735

  468. 468.

    Sandborn, W. J. et al. Tofacitinib for the treatment of ulcerative colitis: an integrated summary of up to 7.8 years of safety data from the global clinical program. J. Crohns Colitis17, 338–351 (2022).

    Not in our library10.1093/ecco-jcc/jjac141

  469. 469.
    Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis · 2022
    No notice
  470. 470.

    You H, et al. Tofacitinib as a possible treatment for skin thickening in diffuse cutaneous systemic sclerosis. Rheumatology. 2021;60:2472-2477.

    Not in our library10.1093/rheumatology/keaa613

  471. 471.

    Khosrow-Khavar F, Desai RJ, Lee H, Lee SB, Kim SC. Tofacitinib and risk of malignancy: results from the safety of tofacitinib in routine care patients with rheumatoid arthritis (STAR-RA) study. Arthritis Rheumatol. 2022;74:1648-1659.

    Not in our library10.1002/art.42250

  472. 472.

    Miyawaki H, et al. Long-term effects of the janus kinase 1/2 inhibitor ruxolitinib on pulmonary hypertension and the cardiac function in a patient with myelofibrosis. Intern. Med. 2020;59:229-233.

    Not in our library10.2169/internalmedicine.3528-19

  473. 473.

    Karpov AA, et al. Inhibition of JAK1,2 prevents fibrotic remodeling of pulmonary vascular bed and improves outcomes in the rat model of chronic thromboembolic pulmonary hypertension. Int. J. Mol. Sci. 2022;23:15646.

    Not in our library10.3390/ijms232415646

  474. 474.
    Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database · 2022
    No notice
  475. 475.

    Genovese MC, et al. Baricitinib in patients with refractory rheumatoid arthritis. N. Engl. J. Med. 2016;374:1243-1252.

    Not in our library10.1056/nejmoa1507247

  476. 476.

    Taylor PC, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann. Rheum. Dis. 2022;81:335-343.

    Not in our library10.1136/annrheumdis-2021-221276

  477. 477.

    Tanaka Y, et al. Clinical outcomes in patients switched from adalimumab to baricitinib due to non-response and/or study design: phase III data in patients with rheumatoid arthritis. Ann. Rheum. Dis. 2019;78:890-898.

    Not in our library10.1136/annrheumdis-2018-214529

  478. 478.

    Smolen JS, et al. Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann. Rheum. Dis. 2017;76:694-700.

    Not in our library10.1136/annrheumdis-2016-209821

  479. 479.

    Lei Y, et al. A multicenter blinded preclinical randomized controlled trial on Jak1/2 inhibition in MRL/MpJ-Fas(lpr) mice with proliferative lupus nephritis predicts low effect size. Kidney Int. 2021;99:1331-1341.

    Not in our library10.1016/j.kint.2021.01.024

  480. 480.

    Wallace DJ, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2018;392:222-231.

    Not in our library10.1016/s0140-6736(18)31363-1

  481. 481.

    King B, et al. Efficacy and safety of the oral Janus kinase inhibitor baricitinib in the treatment of adults with alopecia areata: Phase 2 results from a randomized controlled study. J. Am. Acad. Dermatol. 2021;85:847-853.

    Not in our library10.1016/j.jaad.2021.05.050

  482. 482.

    Simpson EL, et al. Baricitinib in patients with moderate-to-severe atopic dermatitis: results from a randomized monotherapy phase 3 trial in the United States and Canada (BREEZE-AD5). J. Am. Acad. Dermatol. 2021;85:62-70.

    Not in our library10.1016/j.jaad.2021.02.028

  483. 483.

    Guttman-Yassky E, et al. Baricitinib in adult patients with moderate-to-severe atopic dermatitis: a phase 2 parallel, double-blinded, randomized placebo-controlled multiple-dose study. J. Am. Acad. Dermatol. 2019;80:913-921.e919.

    Not in our library10.1016/j.jaad.2018.01.018

  484. 484.

    Bieber T, et al. Efficacy and safety of baricitinib in combination with topical corticosteroids in patients with moderate-to-severe atopic dermatitis with inadequate response, intolerance or contraindication to ciclosporin: results from a randomized, placebo-controlled, phase III clinical trial (BREEZE-AD4). Br. J. Dermatol. 2022;187:338-352.

    Not in our library10.1111/bjd.21630

  485. 485.

    Taylor PC, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N. Engl. J. Med. 2017;376:652-662.

    Not in our library10.1056/nejmoa1608345

  486. 486.

    Kalil AC, et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N. Engl. J. Med. 2021;384:795-807.

    Not in our library10.1056/nejmoa2031994

  487. 487.

    King B, et al. Two phase 3 trials of baricitinib for alopecia areata. N. Engl. J. Med. 2022;386:1687-1699.

    Not in our library10.1056/nejmoa2110343

  488. 488.

    Wolfe CR, et al. Baricitinib versus dexamethasone for adults hospitalised with COVID-19 (ACTT-4): a randomised, double-blind, double placebo-controlled trial. Lancet Respir. Med. 2022;10:888-899.

    Not in our library10.1016/s2213-2600(22)00088-1

  489. 489.

    Ely EW, et al. Efficacy and safety of baricitinib plus standard of care for the treatment of critically ill hospitalised adults with COVID-19 on invasive mechanical ventilation or extracorporeal membrane oxygenation: an exploratory, randomised, placebo-controlled trial. Lancet Respir. Med. 2022;10:327-336.

    Not in our library10.1016/s2213-2600(22)00006-6

  490. 490.

    Marconi VC, et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir. Med. 2021;9:1407-1418.

    Not in our library10.1016/s2213-2600(21)00331-3

  491. 491.

    Stebbing J, et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect. Dis. 2020;20:400-402.

    Not in our library10.1016/s1473-3099(20)30132-8

  492. 492.

    Richardson P, et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395:e30-e31.

    Not in our library10.1016/s0140-6736(20)30304-4

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    Cantini F, et al. Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. J. Infect. 2020;81:318-356.

    Not in our library10.1016/j.jinf.2020.04.017

  494. 494.

    Cantini F, et al. Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study. J. Infect. 2020;81:647-679.

    Not in our library10.1016/j.jinf.2020.06.052

  495. 495.

    Taylor PC, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 2019;71:1042-1055.

    Not in our library10.1002/art.40841

  496. 496.

    Markham A, Keam SJ. Peficitinib: first global approval. Drugs. 2019;79:887-891.

    Not in our library10.1007/s40265-019-01131-y

  497. 497.

    Lee YH, et al. Comparative efficacy and safety of peficitinib 25, 50, 100, and 150 mg in patients with active rheumatoid arthritis: a bayesian network meta-analysis of randomized controlled trials. Clin. Drug Investig. 2020;40:65-72.

    Not in our library10.1007/s40261-019-00863-9

  498. 498.

    Dhillon S. Delgocitinib: first approval. Drugs. 2020;80:609-615.

    Not in our library10.1007/s40265-020-01291-2

  499. 499.

    Worm M, et al. The pan-JAK inhibitor delgocitinib in a cream formulation demonstrates dose response in chronic hand eczema in a 16-week randomized phase IIb trial. Br. J. Dermatol. 2022;187:42-51.

    Not in our library10.1111/bjd.21037

  500. 500.

    Worm M, et al. Efficacy and safety of topical delgocitinib in patients with chronic hand eczema: data from a randomized, double-blind, vehicle-controlled phase IIa study. Br. J. Dermatol. 2020;182:1103-1110.

    Not in our library10.1111/bjd.18469

  501. 501.

    Nakagawa H, et al. Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis. J. Dermatol. 2020;47:114-120.

    Not in our library10.1111/1346-8138.15173

  502. 502.

    Nakagawa H, et al. Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study. J. Am. Acad. Dermatol. 2020;82:823-831.

    Not in our library10.1016/j.jaad.2019.12.015

  503. 503.

    Nakagawa H, et al. Delgocitinib ointment in pediatric patients with atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study. J. Am. Acad. Dermatol. 2021;85:854-862.

    Not in our library10.1016/j.jaad.2021.06.014

  504. 504.

    Nakagawa H, et al. Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis. J. Allergy Clin. Immunol. 2019;144:1575-1583.

    Not in our library10.1016/j.jaci.2019.08.004

  505. 505.

    Garrido-Trigo A, Salas A. Molecular structure and function of janus kinases: implications for the development of inhibitors. J. Crohns Colitis. 2020;14:S713-s724.

    Not in our library10.1093/ecco-jcc/jjz206

  506. 506.

    Nielsen OH, Boye TL, Chakravarti D, Gubatan J. Selective tyrosine kinase 2 inhibitors in inflammatory bowel disease. Trends Pharm. Sci. 2022;43:424-436.

    Not in our library10.1016/j.tips.2022.02.008

  507. 507.

    Pardanani A, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J. Clin. Oncol. 2011;29:789-796.

    Not in our library10.1200/jco.2010.32.8021

  508. 508.

    Pardanani A, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1:643-651.

    Not in our library10.1001/jamaoncol.2015.1590

  509. 509.
    Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure · 2020
    No notice
  510. 510.

    Pardanani A, et al. A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis. Blood Cancer J. 2015;5:e335.

    Not in our library10.1038/bcj.2015.63

  511. 511.

    Harrison CN, et al. Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts. Br. J. Haematol. 2022;198:317-327.

    Not in our library10.1111/bjh.18207

  512. 512.

    Gerds AT, et al. Myeloproliferative neoplasms, version 3.2022, NCCN clinical practice guidelines in oncology. J. Natl. Compr. Cancer Netw. 2022;20:1033-1062.

    Not in our library10.6004/jnccn.2022.0046

  513. 513.

    Conigliaro P, et al. Challenges in the treatment of rheumatoid arthritis. Autoimmun. Rev. 2019;18:706-713.

    Not in our library10.1016/j.autrev.2019.05.007

  514. 514.

    Mahajan S, et al. VX-509 (decernotinib) is a potent and selective janus kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease. J. Pharm. Exp. Ther. 2015;353:405-414.

    Not in our library10.1124/jpet.114.221176

  515. 515.

    Fleischmann RM, et al. A randomized, double-blind, placebo-controlled, twelve-week, dose-ranging study of decernotinib, an oral selective JAK-3 inhibitor, as monotherapy in patients with active rheumatoid arthritis. Arthritis Rheumatol. 2015;67:334-343.

    Not in our library10.1002/art.38949

  516. 516.

    Genovese MC, van Vollenhoven RF, Pacheco-Tena C, Zhang Y, Kinnman N. VX-509 (decernotinib), an oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheumatol. 2016;68:46-55.

    Not in our library10.1002/art.39473

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    Genovese MC, Yang F, Østergaard M, Kinnman N. Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings. Ann. Rheum. Dis. 2016;75:1979-1983.

    Not in our library10.1136/annrheumdis-2015-208901

  518. 518.

    Etra A, et al. Effective treatment of low-risk acute GVHD with itacitinib monotherapy. Blood. 2023;141:481-489.

    Not in our library10.1182/blood.2022017442

  519. 519.

    Zeiser R, et al. Efficacy and safety of itacitinib versus placebo in combination with corticosteroids for initial treatment of acute graft-versus-host disease (GRAVITAS-301): a randomised, multicentre, double-blind, phase 3 trial. Lancet Haematol. 2022;9:e14-e25.

    Not in our library10.1016/s2352-3026(21)00367-7

  520. 520.

    Burmester GR, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018;391:2503-2512.

    Not in our library10.1016/s0140-6736(18)31115-2

  521. 521.

    Duggan S, Keam SJ. Upadacitinib: first approval. Drugs. 2019;79:1819-1828.

    Not in our library10.1007/s40265-019-01211-z

  522. 522.

    Kavanaugh A, et al. Safety and efficacy of filgotinib: up to 4-year results from an open-label extension study of phase II rheumatoid arthritis programs. J. Rheumatol. 2021;48:1230-1238.

    Not in our library10.3899/jrheum.201183

  523. 523.

    Smolen JS, et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet. 2019;393:2303-2311.

    Not in our library10.1016/s0140-6736(19)30419-2

  524. 524.

    Deodhar A, et al. Upadacitinib for the treatment of active non-radiographic axial spondyloarthritis (SELECT-AXIS 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2022;400:369-379.

    Not in our library10.1016/s0140-6736(22)01212-0

  525. 525.

    Danese S, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399:2113-2128.

    Not in our library10.1016/s0140-6736(22)00581-5

  526. 526.

    Gooderham MJ, et al. Efficacy and safety of oral janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial. JAMA Dermatol. 2019;155:1371-1379.

    Not in our library10.1001/jamadermatol.2019.2855

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    Ständer S, et al. High threshold efficacy responses in moderate-to-severe atopic dermatitis are associated with additional quality of life benefits: pooled analyses of abrocitinib monotherapy studies in adults and adolescents. J. Eur. Acad. Dermatol. Venereol. 2022;36:1308-1317.

    Not in our library10.1111/jdv.18170

  528. 528.

    Silverberg JI, et al. Efficacy and safety of abrocitinib in patients with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2020;156:863-873.

    Not in our library10.1001/jamadermatol.2020.1406

  529. 529.

    Eichenfield LF, et al. Efficacy and safety of abrocitinib in combination with topical therapy in adolescents with moderate-to-severe atopic dermatitis: the JADE TEEN randomized clinical trial. JAMA Dermatol. 2021;157:1165-1173.

    Not in our library10.1001/jamadermatol.2021.2830

  530. 530.

    Shi VY, et al. Phase 3 efficacy and safety of abrocitinib in adults with moderate-to-severe atopic dermatitis after switching from dupilumab (JADE EXTEND). J. Am. Acad. Dermatol. 2022;87:351-358.

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    Napolitano M, et al. The efficacy and safety of abrocitinib as a treatment option for atopic dermatitis: a short report of the clinical data. Drug Des. Devel. Ther. 2021;15:1135-1147.

    Not in our library10.2147/dddt.s240866

  532. 532.

    Reich K, et al. Magnitude and time course of response to abrocitinib for moderate-to-severe atopic dermatitis. J. Allergy Clin. Immunol. Pract. 2022;10:e3222.

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  533. 533.

    Simpson EL, et al. Integrated safety analysis of abrocitinib for the treatment of moderate-to-severe atopic dermatitis from the phase II and phase III clinical trial program. Am. J. Clin. Dermatol. 2021;22:693-707.

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  534. 534.

    Chimalakonda A, et al. Selectivity profile of the tyrosine kinase 2 inhibitor deucravacitinib compared with janus kinase 1/2/3 inhibitors. Dermatol. Ther. 2021;11:1763-1776.

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  535. 535.

    Hoy SM. Deucravacitinib: first approval. Drugs. 2022;82:1671-1679.

    Not in our library10.1007/s40265-022-01796-y

  536. 536.

    Armstrong AW, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial. J. Am. Acad. Dermatol. 2023;88:29-39.

    Not in our library10.1016/j.jaad.2022.07.002

  537. 537.

    Strober B, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 Program fOr Evaluation of TYK2 inhibitor psoriasis second trial. J. Am. Acad. Dermatol. 2023;88:40-51.

    Not in our library10.1016/j.jaad.2022.08.061

  538. 538.

    Morand E, et al. Deucravacitinib, a tyrosine kinase 2 inhibitor, in systemic lupus erythematosus: a phase ii, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2023;75:242-252.

    Not in our library10.1002/art.42391

  539. 539.

    Chen B, et al. Efficacy and safety of ivarmacitinib in patients with moderate-to-severe, active, ulcerative colitis: a phase II study. Gastroenterology. 2022;163:1555-1568.

    Not in our library10.1053/j.gastro.2022.08.007

  540. 540.

    Wu H, et al. JAK1-STAT3 blockade by JAK inhibitor SHR0302 attenuates inflammatory responses of adjuvant-induced arthritis rats and decreases Th17 and total B cells. Jt. Bone Spine. 2016;83:525-532.

    Not in our library10.1016/j.jbspin.2015.09.002

  541. 541.

    Sun X, et al. Preventive and therapeutic effects of a novel JAK inhibitor SHR0302 in acute graft-versus-host disease. Cell Transpl. 2021;30:9636897211033778.

    Not in our library10.1177/09636897211033778

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    Zhao Y, et al. Efficacy and safety of SHR0302, a highly selective janus kinase 1 inhibitor, in patients with moderate to severe atopic dermatitis: a phase II randomized clinical trial. Am. J. Clin. Dermatol. 2021;22:877-889.

    Not in our library10.1007/s40257-021-00627-2

  543. 543.

    Su, Q. et al. Discovery of (2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide (AZD4205) as a potent and selective janus kinase 1 inhibitor. J. Med. Chem. 63, 4517–4527 (2020).

    Not in our library10.1021/acs.jmedchem.9b01392

  544. 544.

    Tefferi A, Gangat N, Pardanani A. Jaktinib (JAK1/2 inhibitor): a momelotinib derivative with similar activity and optimized dosing schedule. Am. J. Hematol. 2022;97:1507-1509.

    Not in our library10.1002/ajh.26712

  545. 545.
    A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Ascending Dose and Food Effect Study to Evaluate the Tolerance, Pharmacokinetics of Jaktinib, a New Selective Janus Kinase Inhibitor in Healthy Chinese Volunteers · 2020
    Not checked
  546. 546.

    Zhang Y, et al. Safety and efficacy of jaktinib in the treatment of Janus kinase inhibitor-naïve patients with myelofibrosis: results of a phase II trial. Am. J. Hematol. 2022;97:1510-1519.

    Not in our library10.1002/ajh.26709

  547. 547.

    Meng X, et al. Potential for jaktinib hydrochloride to treat cytokine storms in patients with COVID-19. Biosci. Trends. 2020;14:161-167.

    Not in our library10.5582/bst.2020.03106

  548. 548.

    Philips RL, et al. The JAK-STAT pathway at 30: much learned, much more to do. Cell. 2022;185:3857-3876.

    Not in our library10.1016/j.cell.2022.09.023

  549. 549.

    Thoidingjam LK, et al. Small Molecule Inhibitors of Interferon-Induced JAK-STAT Signalling. Angew. Chem. Int. Ed. Engl. 2022;61:e202205231.

    Not in our library10.1002/anie.202205231

  550. 550.

    Pohóczky K, et al. Discovery of novel targets in a complex regional pain syndrome mouse model by transcriptomics: TNF and JAK-STAT pathways. Pharm. Res. 2022;182:106347.

    Not in our library10.1016/j.phrs.2022.106347

  551. 551.

    Patterson H, Nibbs R, McInnes I, Siebert S. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin. Exp. Immunol. 2014;176:1-10.

    Not in our library10.1111/cei.12248

  552. 552.
    Clinical significance of Janus Kinase inhibitor selectivity · 2018
    No notice
  553. 553.

    Lin CM, Cooles FA, Isaacs JD. Basic mechanisms of JAK inhibition. Mediterr. J. Rheumatol. 2020;31:100-104.

    Not in our library10.31138/mjr.31.1.100

  554. 554.

    Cook N, Hansen AR, Siu LL, Abdul Razak AR. Early phase clinical trials to identify optimal dosing and safety. Mol. Oncol. 2015;9:997-1007.

    Not in our library10.1016/j.molonc.2014.07.025

  555. 555.

    Pérez-Jeldres T, et al. Targeting cytokine signaling and lymphocyte traffic via small molecules in inflammatory bowel disease: JAK inhibitors and S1PR agonists. Front. Pharm. 2019;10:212.

    Not in our library10.3389/fphar.2019.00212

  556. 556.
    New biologics and small molecules in inflammatory bowel disease: an update · 2019
    Not checked
  557. 557.

    Chen CX, et al. JAK-inhibitors for coronavirus disease-2019 (COVID-19): a meta-analysis. Leukemia. 2021;35:2616-2620.

    Not in our library10.1038/s41375-021-01266-6

  558. 558.

    Kleppe M, et al. Dual targeting of oncogenic activation and inflammatory signaling increases therapeutic efficacy in myeloproliferative neoplasms. Cancer Cell. 2018;33:29-43.e27.

    Not in our library10.1016/j.ccell.2017.11.009

  559. 559.

    Pastore F, et al. PRMT5 inhibition modulates E2F1 methylation and gene-regulatory networks leading to therapeutic efficacy in JAK2(V617F)-mutant MPN. Cancer Discov. 2020;10:1742-1757.

    Not in our library10.1158/2159-8290.cd-20-0026

  560. 560.

    Blair HA. Fedratinib: first approval. Drugs. 2019;79:1719-1725.

    Not in our library10.1007/s40265-019-01205-x

  561. 561.
    Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis · 2020
    No notice
  562. 562.

    Zhang W, et al. Mutant FLT3: a direct target of sorafenib in acute myelogenous leukemia. J. Natl. Cancer Inst. 2008;100:184-198.

    Not in our library10.1093/jnci/djm328

  563. 563.

    Fridman JS, et al. Preclinical evaluation of local JAK1 and JAK2 inhibition in cutaneous inflammation. J. Invest. Dermatol. 2011;131:1838-1844.

    Not in our library10.1038/jid.2011.140

  564. 564.
    Novel and Emerging Therapies for Inflammatory Bowel Disease · 2021
    No notice

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