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JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens

Qian Hu, Qihui Bian, Dingchao Rong and 6 more

Frontiers in Bioengineering and Biotechnology · 2023 · Review · CC BY

doi:10.3389/fbioe.2023.1110765

Abstract

Janus kinase/signal transduction and transcription activation (JAK/STAT) pathways were originally thought to be intracellular signaling pathways that mediate cytokine signals in mammals. Existing studies show that the JAK/STAT pathway regulates the downstream signaling of numerous membrane proteins such as such as G-protein-associated receptors, integrins and so on. Mounting evidence shows that the JAK/STAT pathways play an important role in human disease pathology and pharmacological mechanism. The JAK/STAT pathways are related to aspects of all aspects of the immune system function, such as fighting infection, maintaining immune tolerance, strengthening barrier function, and cancer prevention, which are all important factors involved in immune response. In addition, the JAK/STAT pathways play an important role in extracellular mechanistic signaling and might be an important mediator of mechanistic signals that influence disease progression, immune environment. Therefore, it is important to understand the mechanism of the JAK/STAT pathways, which provides ideas for us to design more drugs targeting diseases based on the JAK/STAT pathway. In this review, we discuss the role of the JAK/STAT pathway in mechanistic signaling, disease progression, immune environment, and therapeutic targets.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 18, 2026. Paragraph numbers are ours, so an answer can point at one.

1 Introduction

1Studies have shown that activation of the JAK/STAT pathway promotes the development and progression of various diseases, including various inflammatory diseases, lymphomas, leukemias, various solid tumors, and so on. Their relationship and mechanisms have become crucial for the treatment of various diseases. The JAK/STAT pathway is an important cascade of signal transduction for multiple growth factors and cytokines, which regulates gene expression and cell activation, proliferation, and differentiation.

2The JAK/STAT pathway has three components: cellular receptors, JAK protein, and STAT protein. The JAK family is a group of non-transmembrane tyrosine kinases, which is mainly composed of four members: JAK1, JAK2, JAK3, and TYK2 with molecular weights ranging from 120 to 140 kDa. JAK1, JAK2, and TYK2 are ubiquitous, while JAK3 is mainly expressed in hematopoietic cells. There are seven members of the STAT family in a mammal: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. Each member of the STAT family can be activated by a variety of cytokines and associated JAKs. First, cytokines bind to the corresponding transmembrane receptors and induce dimerization then activating JAK kinases couple to and phosphorylate the receptors. Second, the tyrosine residues on the catalytic domain of the receptor are phosphorylated to form a docking site in which STAT proteins with SH2 domains are recruited to this docking site, and STATs are phosphorylated and form homodimers or heterodimers. Finally, dimerized STATs dissociate from receptors and translocate into the nucleus, where they bind to DNA-binding sites and regulate gene transcription. Therefore, the activation of the JAK/STAT signaling cascade pathway is necessarily influenced by upstream extracellular cytokines and downstream JAK/STAT family protein types. For example, IFN-α/β activate STAT1, STAT2, and STAT4 via JAK1 and TYK2, whereas IFN-γ actives STAT1 or STAT5 via JAK1 and JAK2. IL-6 and IL-11 activate STAT1, STAT3 via JAK1, JAK2, and TYK2, but IL-12 and IL-23 activate STAT3 and STAT4 via JAK2 and TYK2. At the same time, STAT can be directly activated independently of JAK pathways, such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and mitogen-activated protein kinase (MAPK). In addition, the JAK/STAT pathway receives regulation by multiple mechanisms, including that PIAS inhibits gene transcription by directly binding to STAT dimers and thereby blocking STAT binding to DNA. And SOCS protein can negatively regulate the JAK/STAT signaling cascade by inhibiting JAK activity, competing with STAT to bind phosphorylation sites on cytokine receptors, and inducing STAT proteasomal degradation (Figure 1).

2 JAK/STAT pathway in disease progression

3The JAK/STAT signaling axis is a central pathway that mediates the cellular inflammation response, and carcinogenesis, and participates in the transduction of cellular physiological signals, such as renin-angiotensin signaling, insulin-like growth factor (IGF-IR) signaling (Figure 2). STAT promotes the transcriptional activation of target genes in response to specific extracellular stimuli (including cytokines, growth factors, and other agents) through tyrosine phosphorylation-mediated activation, most of which is mediated by JAKs, but with the interaction of multiple intracellular signaling proteins, then affecting key cellular processes, including differentiation, proliferation, survival and functional activation, which in turn are involved in the development of various diseases.

2.1 JAK/STAT pathway in oncopathology

4In oncology research, JAK/STAT is attracting more and more attention, increasingly studies show that STAT3 is constitutive activated in tumors and involved in cellular carcinogenesis. The pathway is involved in a variety of malignant tumors, including leukemia, multiple myeloma, lymphoma, head and neck cancer, colon cancer, gastric cancer, hepatocellular carcinoma, pancreatic cancer, breast cancer, melanoma, ovarian cancer, lung cancer and prostate cancer.

5Cancer stem cells (CSCs), a subpopulation of tumor cells with stem cell properties that self-renew and give rise to a variety of more differentiated cells, are a key driver of tumor progression. Studies have shown that cancer stem cells have been proposed to explain the development of cancer and resistance to treatment, and activation of the JAK/STAT signalling pathway, or induction of other signals that interact with the JAK/STAT pathway, can promote the production and acquisition of drug resistance by cancer stem cells. Researches show that STAT3 is critical for tumor transformation downstream of oncogenes Src and Ras. Src induces tyrosine phosphorylation and transcriptional activity of STAT3, and Ras phosphorylates STAT3 at Serine 727, which is required for localization to mitochondria. In turn, mitochondrial STAT3 supports Ras oncogenic transformation by supporting a metabolic shift. Cao et al. found that STAT3 was consistently activated in Src-transformed cell lines, and the interruption of the STAT3 signal blocked the transformation of mouse fibroblasts by Src oncoprotein. Furthermore, it has been reported that oncogenes such as Bcr-Abl, v-Eyk, v-Ros, and v-Fps may play similar functions. JAK/STAT pathways are also involved in various aspects of tumor development, such as invasion and metastasis. For example, abnormal activation of IL-6-mediated JAK/STAT3 signal transduction frequently occurs in human cancers and is involved in transformation, tumorigenicity, EMT, and metastasis. IL-6/JAK2/STAT3 activation induces EMT by up-regulating EMT-induced transcription factors (EMT-TFs, Snail, Zeb1, JUNB, and Twist-1), and enhances cell motility by activating focal adhesion kinase (FAK), which enhances metastasis. Xiao et al. demonstrated that IL-6 can promote EMT in peritoneal mesothelial cells, which is related to the activation of the JAK/STAT pathway. Furthermore, reviews have concluded the effects of JAK/STAT3 activation on EMT by multiple intracellular signals protein, including PTK6, Williamʹs syndrome transcription factor (WSTF), Pin1, PYK2, SMAD4, RAC1, and other signals protein. NF-κB signaling has been identified as a major pathway to induce inflammation in tumors, where STAT3 directly interact with NF-κB family members to capture it in the nucleus, thereby promoting constitutive activation of NF-κB, leading to many oncogenic and inflammatory genes activations. Ruan et al. found that overexpression of OCT4 (a marker for cancer stem cells in ovarian cancer) increased the activation of the JAK/STAT pathway, especially JAK1 and STAT6, and promoted the translocation of STAT6 from the cytoplasm to nuclear in non-SP cells (CSC-like side population cells), thereby increasing the expression of Cyclin D1, c-Myc, and Bcl-2. As mentioned earlier, JAK/STAT can be activated by a variety of cytokines, thereby transducing and activating a variety of downstream signaling pathways in cells (Figure 2).

6Activated JAKs also induces the activation of other downstream signaling cascades, including the MAPK and PI3K/AKT pathways. Studies demonstrate that ERK signaling regulates MHC II expression in spinal cord microglia through regulation of the STAT1 phosphorylation and promotes bone cancer pain. AMPK inhibits tumor proliferation by suppressing STAT3 activation. Furthermore, STAT5 was found to form a complex with ERK1/ERK2 in colorectal cancer cells, suggesting a cross-talk between STAT5 and MAPK signaling pathways in the development of human colorectal cancer. However, another recent study showed the presence of STAT5 in PI3K immunoprecipitation in leukemic bone marrow cells, but no STAT5-PI3K complexes were found in CRC cells. The specific cell type and tumor microenvironment may explain this phenomenon. It has been reported that STAT3 down-regulates the expression of important proteins related to apoptosis induction, including P53, IFN-β, Fas and its ligands, and BAX. Abnormal activation of STAT3 also leads to abnormal overexpression of various proteins, including Mcl-1, Bcl-2, Bcl-xl, survivin, Cyclin D1, c-Myc, and VEGF, which leads to tumor development. In Barbara’s review, he mentioned that STAT was related to autophagy. PKR-eIF2A pathway is an important inducer of autophagy, and STAT3 inactivates this pathway through binding to PKR and inactivation of eIF2A phosphorylation. In addition to STAT3, constitutive activation of STAT1 and STAT5 was also shown in tumor cells and tumor tissues. In chronic myeloid leukemia (CML) and myeloproliferative diseases induced by TEL-JAK2, STAT5 is activated by a variety of hematopoietic and non-hematopoietic cytokines and growth factors to promote the development of these tumors. However, activation of STAT1 usually appears to promote tumor cell apoptosis and anti-proliferative effects. Tumors are more likely to develop in STAT1-deficient mice. However, some studies have also shown that STAT1 can induce platinum resistance in breast cancer, which may be independent of the activation of JAK2/3.

7In summary, the JAK/STAT pathway is involved in the activation and transduction of various signaling pathways related to tumorigenesis and development, suggesting that the JAK/STAT pathway may be another new target for cancer treatment.

2.2 JAK/STAT pathway in other diseases

8Recent studies have shown the involvement of JAK/STAT in multiple diseases and their physiological processes. For example, studies have found that RA phosphorylates JAK2 by binding to AT1, thereby activating JAK and STAT signaling pathways to mediate VCSM growth, migration, and remodeling. IGF-IR exerts signaling effects by activating the JAK/STAT pathway. A study unveiled that miR-326 targets MDK to regulate the progression of cardiac hypertrophy by blocking JAK/STAT and MAPK signaling pathways. Melatonin may have protective and therapeutic effects on hypercholesterolemia by regulating vaspin, STAT-3, DDAH, and ADMA signaling pathways. Increased levels of STAT-1 promote SMC (Smooth muscle cell) de-differentiation, whereas high levels of STAT-3 drive SMC into a more mature phenotype. Therefore, the study of the JAK/STAT pathway can help us gain a deeper understanding of the pathological and pharmacological mechanisms of multiple diseases.

3 JAK/STAT signaling regulation of the immune environment

9The role of the JAK/STAT pathway is critical in immune regulation which has attracted increasing attention. STAT transcription factors were regulated by many cytokines, so as to control the immune response and induce tumor immune escape, promote or inhibit the expansion and activation of various immune cells (Table 1).

3.1 MDSC immunosuppressive function

10As we know, Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells and have immunosuppressive properties for adaptive immunity and innate immunity. MDSCs are derived from hematopoietic stem cells in bone marrow. Signals from tumors and inflammatory tissues stimulate the differentiation of IMC (immature myeloid cells, the progenitors of MDSCs) to MDSC through the STAT pathway and promote their expansion. Kim’s review has elucidated that VEGF, G-CSF, GM-CSF, Flt3L, and other anti-inflammatory cytokines (IL-4, IL-6, IL-10) can activate STAT signaling and thus regulate MDSC proliferation and activation. IL-6, IL-10, and VEGF can activate STAT3 on MDSC, which can enhance the number of MDSC. MDSCs immunosuppressive mechanisms may be related to the expression of arginase-I, IDO, iNOS, and PD-L1 by JAK-STAT3 signals activation. STAT1 is a major transcription factor for IFN-γ mediated signaling activation and is involved in the upregulation of arginase 1 and iNOS expression by MDSCs. For example, research has shown that blocking IFN-γ or disrupting STAT1 partially impaired suppression by MO-MDSCs. Activation of STAT6 by IL-4, and IL-13 leads to activation of MDSC, which causes upregulation of arginase 1, inducible iNOS, and production of transforming growth factor-β (TGFβ), which then increases the suppressive function of MDSCs.

3.2 DC development

11Dendritic cells (DC) are discrete cell populations derived from hematopoietic stem cells (HSCs) and have important functions in immune surveillance. DCs are produced by hematopoietic progenitor cells (such as CDP) under the control of exogenous cytokine signals and intrinsic transcriptional regulators. The main cytokines involved in DC development include Flt3L, GM-CSF, and IFN-α, which respectively stimulate STAT3, STAT5, and STAT1, and each STAT has a different role in DC production. Studies have shown that STAT3 activation is an important factor for Flt3L to regulate DC development, and the absence of STAT3 in hematopoietic cells eliminates the effect of Flt3L on DC. Under steady-state conditions, GM-CSF regulates the generation of CD103+DC by inducing STAT5-ld2 signal activation. STAT5 is considered to be the major GM-CSF response signal protein. Studies have shown that GM-CSF used STAT5 to prevent the development of Flt3L-dependent pDC from the lineage-negative Flt3+ (lin− Flt3+) bone-marrow subset. STAT1-mediated IFNα promotes the proliferation of HSCs and then differentiates into CDP. IL-6 is the main cytokine controlling DCs differentiation in vivo. IL-6 mediates the inhibitory effect of bone marrow-derived DC maturation by regulating STAT3 phosphorylation in DC cells. The inhibitory effect of STAT3 on DC maturation may also be caused by VEGF and IL-10 signaling. The functions of DC, T cells, natural killer (NK) cells, and neutrophils are significantly enhanced in tumor-bearing mice with Stat3−/− hematopoietic cells.

3.3 NK cell function

12Natural killer (NK) cells are an important early effector in the innate immune system to resist multiple viral infections and eliminate tumor cells. IL-15 is required for the maturation of NK cells at all stages of development. In Nguyen’s experiment, they found that in a virus-infected mouse model, the maintenance of IFNα/β on the accumulation of proliferative NK cells is mainly dependent on the production of IL-15 induced by STAT1. In mice deficient in STAT1, T-bet, or MHC type I molecules, the maturation state of peripheral NK cells is impaired, and they are more sensitive to viral and bacterial infections. STAT3 can also indirectly damage the function of NK cells by regulating the expression of NK cell activation receptor ligands and immune checkpoint proteins, such as NKG2D ligand MICA, PD-L1. In a mouse model, STAT3-deficient NK cells enhance tumor immune surveillance and increase DNAM-1 and the lytic enzymes perforin and granzyme B secretion. STAT5a and STAT5b are important transcription factors for the activation, proliferation, and maturation of NK cells in humans and mice. STAT5b-deficient NK cells have decreasing proliferation and toxicity after stimulation by IL-2 and IL-15, and circulating NK cells in STAT5b-deficient patients are also significantly reduced, resulting in low cytotoxicity.

3.4 T cells

13T cells are derived from lymphatic stem cells in the thymus. They are the most numerous and complex type of cells in lymphocytes that produce cellular immunity. IL-6 and IL-10 cytokines activate STAT3 on T cells, which is usually related to poor cytotoxicity and anti-tumor immune response. Studies have shown that IL-6 mediates the differentiation of naive CD4+ T cells into inflammatory Th17 cells through STAT3, while IL-10 targeting IL-10Rα has similar effects. Furthermore, studies showed that IL-6 maintains the mitochondrial membrane potential during CD4+ cell activation in a STAT3-dependent manner, thereby increasing mitochondrial Ca+ levels and promoting cytokine expression. Studies found that STAT3 bound to multiple genes involved in Th17 cell differentiation by using chromatin immunoprecipitation and massive parallel sequencing (ChIP-Seq). STAT3 and FoxP3 can be used as transcription factors to regulate the biological function of Treg. IL-12 induces a high intensity of tumor-specific CTL activity in STAT1-deficient mice, increases the CD8+ T-cell density, and induces a T-cell-dependent tumor regression. IL-2-induced FOXP3 expression in human Treg cells is mediated by STAT signaling, including both STAT3 and STAT5. STAT5 also can combine with the FoxP3 gene promoter, regulate FoxP3 expression, and promote Treg differentiation. The phosphorylation of STAT3 by IL-6 will inhibit the Th9 cell differentiation, which was mediated by the suppression of IL-2 production and STAT5 signaling. IL-2 selectively up-regulated the expression of FOXP3 in purified CD4+CD25+ T cells which involved the binding of STAT3 and STAT5 proteins. And present data demonstrate that CD4+CD25+FoxP3+ regulatory T cells impede dendritic cell function which requires TGF-beta and IL-10 by activating STAT3. Furthermore, IL-12 is able to transcriptionally regulate STAT4 and thus participated in the development and differentiation of Th1 cells and STAT6-deficient T lymphocytes failed to differentiate into Th2 cells despite under IL-4 stimulation. Activation of the IFNγ/STAT1/IRF1 axis favors processing and the presentation of tumor antigens, in association with MHC class I or class II molecules. Research has shown that endogenously secreted IFNs served to antagonize stress-dependent expansions of T cells through a STAT2-dependent pathway. In addition, STAT1 hyper-phosphorylation can lead to impaired IL-23 signaling, which can in turn result in defective Th17 T cell responses.

14Members of the STAT protein family are involved in regulating immune responses in the tumor microenvironment, including pro-tumor or anti-tumor inflammatory responses. On the one hand, abnormal STAT3 expression in tumors is correlated with MDSC and Th17 levels, affecting DCs and thus affecting anti-tumor response. IL-6 induces STAT3-mediated Th17 differentiation, which maintains inflammatory responses by releasing IL-17 and IL-23 and causes the secretion of VEGF and TGF in fibroblasts and endothelial cells. STAT3-mediated IL-23 production also inhibited the proliferation of effector T cells. STAT3 also regulates the expression of PD-L1 on antigen-presenting cells which affects the drug effect of immunotherapy.

3.5 Indirect effects on immune cells

15A study found that STAT3-mediated IL-10 secretion can promote the formation of M2 macrophages, and M2 macrophages regulate the function of breast cancer stem cells through EGFR/STAT3/SOX-2 paracrine signals. IL-4 induces pSTAT6-mediated inhibition of the activation of multiple genes involved in alternative macrophage polarization, such as NLRP3 and IL-1B, thereby inhibiting inflammasome stimulation and pyroptosis. In tumor-associated macrophages (TAMs), STAT1 regulates the expression of arginase and NO, which in turn suppresses T cell-mediated immune responses and induces T cell apoptosis. On the other hand, inactivated STAT3 in hematopoietic stem cells shows an anti-tumor effect, inhibiting tumor growth and metastasis by affecting the activation of DC, T, and NK cells. The absence or targeting of STAT3 in myeloid cells can enhance CD8+ T cell responses and activate tumor-associated monocytes and DC cells, leading to anti-tumor responses, and inhibiting the pro-angiogenic factors VEGF, bEGF, MMP9, CXCL2 secretion, thereby inhibiting the formation of vascular-like structures. In addition, STAT1 is involved in the early development of B cells.

4 Extracellular cytokines affecting the JAK/STAT pathway

16Many cytokines activate the JAK/STAT pathway, which transmits signals directly to the nucleus to induce various cellular responses (Figure 3). Below we describe the various cytokines and proteins that affect the JAK/STAT pathway and the various cellular activities to understand how the JAK/STAT pathway is involved in disease development and thus suggest more effective therapeutic approaches.

4.1 Interleukin in JAK/STAT pathway

17Cytokines of the interleukin family are involved in multiple aspects of cellular life activity functions, including the immune system, physiological functions, inflammatory responses, and cellular metabolism, and all interferons activate members of JAK and STAT. It was shown that IL-6 activated gp130 leading to activation of the JAK/STAT pathway and the IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer. Studies showed that IL-6 downregulated PTPRO expression leading to enhance PD-L1 secretion in monocytes and macrophages through the JAK2/STAT1. IL-4 and IL-13 activate JAK1 by binding to receptors, and JAK1 phosphorylates STAT6, thereby mediating their pulmonary fibrotic effects, while IL-6 induced fibrosis by activating STAT3. Chemokines trigger receptor dimerization, followed by association and activation of JAK proteins. IL-12 is the main driver of STAT4 activation and crucial for IFN-γ production in NK cells. Studies showed that IL-23 induces IL-17A expression in macrophages through the STAT3 and requires STAT4 for IL-17 secretion from memory T helper cells and NKT cells. IL-10 and its subfamily member cytokines IL-19, IL-20, and IL-22 are involved in immune regulation and inflammatory responses by inducing the STAT3 signal transduction pathway. IL-2 family cytokines including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 are involved in NK cell development by activating different JAKs and STATs. IL-27 mediates signaling predominantly through STAT1 and STAT3 and acts in immune-regulatory functions.

4.2 Other cytokines in JAK/STAT pathway

18Cytokines bind to receptor proteins on the cell membrane, activating the downstream JAK/STAT pathway or directly recruiting STAT protein without JAK involvement. Type 1 interferons IFN-α and -β signal bind to their membrane subunits IFNAR1 and IFNAR2 expressed on all cells, then triggering JAK1 and TYK2 phosphorylation and thus recruiting STAT1 and STAT2 monomers for their dimerization activation, thereby facilitating the initiation of dendritic cells (DC) required for T cell activation, supporting immune cell migration, stimulation, and differentiation, as well as inducing regulation of the PI3K/AKT/mTOR signaling pathway. Similar to type 1 interferon IFN, IFN-γ signals through two transmembrane receptor subunits, IFNR1 and IFNR2, activating receptor-associated JAK, leading to the selective recruitment of STAT1, which stimulates the toxic function of CD8+ T cells and NK cells, as well as promoting macrophage polarization toward the M1 phenotype. Other studies in human fibroblasts showed that JAK2 has been activated by TGFβ1, then, in turn, phosphorylates STAT3 and leads to its nuclear translocation. Tumor-derived GM-CSF activated neutrophils and induced neutrophil PD-L1 expression via the JAK-STAT3 pathway. The effects of EPO, TPO, G-SCF, GH, and Leptin are mainly mediated by JAK2 and mainly STAT5. Activation of angiotensin II (AT1) receptors has also been shown to phosphorylate STAT 1, 2, and 3. Studies have demonstrated that STRA6, a plasma membrane protein, can act as a cell factor receptor that mediates the transport of retinol from serum RBP into cells to activate JAK2/STAT5 signaling. Studies showed that CCR2 tyrosine phosphorylation is associated with the JAK and STAT1/3 pathway at different stages of rat adjuvant-induced arthritis (AIA), as well as with macrophage and endothelial cell infiltration. Studies indicated that JAK1 is a downstream tyrosine kinase in PDGF receptor signaling and is a candidate for activation of STAT1. Furthermore, the expressions of PDGFRβ, JAK2, and STAT3 can be inhibited by AG490. It was also found that in vitro PDGF-induced STAT5 activation was directly mediated by PDGFβ-R and its activation did not require JAK1, JAK2, c-Src, Fyn. EGF-R is a transmembrane protein tyrosine kinase and EGF can direct activation of STATs by EGFR binding and indirect activation of STATs through Src-mediated EGFR signaling. EGF induces activation of STAT1, STAT3, and STAT5 in a variety of EGFR overexpressing cells. The study showed no phosphorylation of JAK kinase after the addition of VEGF, suggesting that STAT activation is induced by the intrinsic tyrosine kinase activity of VEGFR. In conclusion, the JAK/STAT pathway is involved in multiple signaling cascades of life activities, and targeting these signaling may provide new ideas for disease treatment.

5 The effect of biophysical forces on the JAK/STAT pathway

19\Cells can sense their extracellular environment and respond to chemical, optical, thermal, and biophysical forces signals, which can affect downstream cellular signaling pathways via second messenger cascades. Ultimately, these changes alter cell behavior and functions. Unlike the effects of drug stimulation or gene editing on cellular activity and pharmacological responses, cells are often subjected to continuous and weak mechanical forces from the surroundings. Even various cell-ECM interactions and 3D cell culture systems have specific biophysical forces. These physical interactions continuously transmit extracellular signals to the cell nucleus, which have multiple and profound effects on numerous biological processes including membrane proteins, intracellular organelles, nuclear transcription and translation processes, and intracellular phase separation.

5.1 Biophysical forces in regulating the JAK/STAT pathway

20The most common biophysical forces applied to mammalian cells are compression, stretching, shear stress, substrate stiffness, and substrate surface patterns, which lead to morphological changes, cell membrane deformation, membrane protein conformational changes, and ultimately triggering downstream signalings. While cytoskeletons, ion channels, integrin receptors, G protein-coupled receptors, a transmembrane protein, and primary cilia are transit points for mechanical signals and often influence the activation of downstream JAK/STAT pathways (Figure 4).

21The study of biophysical forces in adult bone differentiation has been of interest, with several studies demonstrating that aged osteoblasts are characterized by impaired mechanosensitivity, and Cui et al. identified changes in the JAK/STAT pathway after transcription of the osteoblast transcriptome by transcriptomics. For the past few years, Jiliang Li has suggested that the JAK/STAT pathway plays an important role in bone development and metabolism, and that STAT3 has a more profound impact on bone homeostasis compared with other type of STATs. Similarly, Natalie A Sims also held the same views and believed that the JAK1/STAT3/SOCS3 axis featured in bone development, physiology and pathology. Meanwhile, recent studies have shown that mechanical stimulation improves rotator cuff tendon-bone healing by activating IL-4/JAK/STAT signaling pathway mediated macrophage-M2 polarization. All in all, these studies indicate that JAK/STAT pathway plays an important role in bone development and repair.

22Other types of biophysical forces such as extracellular matrix (ECM) stiffness, cell geometry, and shear stress were explored to activate JAK/STAT pathway signaling through activation of associated G proteins as well as rearrangement of the actin cytoskeleton. Fong et al. found that mechanical shear stress can down-regulate PDGF and thus modulate biological responses, a phenomenon that may be related to PDGF stimulation of primary cilia to induce STAT pathway activation. Static mechanical compressive forces lead to IL6 expression, and IL6 may subsequently indirectly activate STATs and translocate them to the nucleus through the JAK. Also, it has been reported that cyclically stretch could induce the expression of MMP-14 and -2 in neonatal rat cardiomyocytes through JAK-STAT1 pathway. Braile and Jayaraman et al. found that pulsatile stretching can stimulate VEGF production in cardiomyocytes (CM) and that VEGF receptors can activate STAT phosphorylation, indirectly affecting downstream signaling via the JAK/STAT pathway. In addition, Liang et al. also found that mechanical stretching-induced upregulation of VEGF-A in human mesenchymal cells was also associated with the JAK/STAT pathway, further illustrating the effect of biophysical forces on the JAK/STAT pathway.

5.2 JAK/STAT pathway mediates the role of biophysical forces

23Current studies have shown that JAK/STAT-mediated mechanotransduction often has important effects on cell physiological processes. Matthews et al. found that mechanical stretch could affect the calcium influx by acting on β1 integrin and that Ca2+ plays a key role in stretch-induced activation of STATs, which has implications for cell and tissue development. The research of Xiao et al. claimed that mechanical stretching-induced vascular endothelial growth factor A upregulation was related to the Janus kinase/signal transducer and activator of transcription (JAK/STAT) and Wnt signaling pathway. Researchers using mechanical stretching of human osteoblasts found that the stretching could upregulate Runx2 gene expression by enhancing the PC1-JAK2/STAT3 signaling axis, which has a decisive effect on bone remodeling. Others showed that mechanical stress induced CCL2 to bind to CCR2 to regulate the production of osteoclasts in pressure grooves and mediated chemotaxis and migration induction through activation of the JAK/STAT pathway in vitro and in vivo. He et al. found that mechanical stress in chondrocytes combined with IL-4 to induce CITED2 gene expression in human chondrocytes via JAK/STAT pathway, thereby inhibiting matrix metalloproteinase (MMP13) production and providing chondroprotection against osteoarthritis (OA). In addition, Qin et al. also found that periodontal ligament stem cells (PDLSC) sensitive to mechanical loading may downregulate HHIP-AS1 and promote the osteogenic differentiation potential of PDLSCs under continuous compressive stress, possibly via the JAK/STAT pathway. The Zyxin/Ajuba family of LIM proteins is a class of proteins that responds to biophysical forces, and Ajuba can play an important role in cell migration and epithelial morphogenesis by separating JAK1 from the interferon receptor and acting as a bona fide inhibitor of IFN/JAK1/STAT1 function. Machida et al. found that cyclic tensile strain induced the expression of ADAMTS4, ADAMTS5, and MMP13 in human chondrocytes via the underlying JAK/STAT pathway.

24Mechanical stretch studies on rat cardiomyocytes by Pan et al.found that mechanical stretch-induced cardiomyocyte hypertrophy, which was largely dependent on cytokines of the IL-6 family, with activation of the JAK/STAT (mainly JAK1/STAT1, STAT3, partially binding to JAK2 and TYK2) pathway mediated by its receptor gp130. Additionally, studies have shown that renal epithelial cells are subjected to flow-induced shear stress within the nephron and that kidney disease is affected by activation of the JAK/STAT pathway, as found by RNA sequencing. Honsho et al. found that pressure-mediated hypertrophy and mechanical stretch produced a low-level expression of IL-1β (subinflammatory), whereas JAK/STAT pathway-mediated production of IGF-1 could maintain its adaptive compensation for hypertrophy and inhibition of interstitial fibrosis. Otherwise, in the neurodevelopmental process, Ciliary neurotrophic factor (CNTF) could directly stimulate JAK-STAT and RAS-MAPK cascaded reactions, and STAT3 signaling was considered as a potential component of neural response to stress stimuli. More interestingly, it has been demonstrated that mechanical stress stimulates cellular immune response through JAK/STAT signaling pathway in Drosophila larvae. In addition, other immunological studies have illustrated that the FTO/SOCS1/YTHDF1 regulatory axis was vital to the stiffness-controlled macrophage inflammatory response, including the culture environment of hydrogel with higher hardness could inhibit the expression of FTO gene through JAK-STAT and NF-κB signals.

25In conclusion, biophysical forces occupy an important role in the induction of downstream signaling in the JAK/STAT pathway, playing a crucial role in the development of individual tissues, including bone, liver, heart, brain, nerves and immune regulation.

6 Clinical status of JAK/STAT pathway inhibitors

26Based on the critical role of JAK/STAT in disease pathology and pharmacology, it is not surprising that inhibitors targeting JAK/STAT have been proposed to treat these diseases. Many inhibitors based on the JAK/STAT pathway have entered preclinical studies and clinical trials in a variety of diseases to evaluate their safety and clinical efficacy.

6.1 JAK/STAT inhibitors

27At present, a variety of inhibitors targeting the JAK/STAT pathway have been used clinically, mainly for the treatment of rheumatoid arthritis, canine dermatitis, psoriasis, ulcerative colitis, myelofibrosis, polycythemia vera, and Primary thrombocytosis (Table 2). Ruxolitinib, a JAK inhibitor, has been identified by the FDA as a clinical treatment for Polycythemia, myelofibrosis, chronic graft-versus-host disease (cGVHD), and Atopic dermatitis by targeting JAK1 and JAK2. A number of clinical trial studies are also validating its efficacy and safety for the treatment of other diseases such as Chronic myelomonocytic leukemia (CMML), peripheral T-cell lymphoma (PTCL), lichen planus, and COVID-2019. The JAK inhibitor Tofacitinib is approved by the FDA as a treatment for rheumatoid arthritis, and it has also been used to study its effectiveness in Psoriasis, ulcerative colitis, juvenile idiopathic arthritis (JIA), transplant rejection, systemic sclerosis (SSc), Sarcoidosis, systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS). Investigators are enrolling patients in a Phase IV clinical study of baricitinib for the treatment of Rheumatoid Arthritis, which is expected to become the standard of care for RA (NCT05238896). Oclacitinib is another inhibitor that targets JAK1 and is used to treat Canine allergic dermatitis. Preclinical studies have shown that specific JAK2 inhibitors can inhibit the growth of tumors in vivo, including pancreatic cancer, colorectal cancer, gastric cancer, liver cancer, lung cancer, ovarian cancer, and breast cancer. Mohrherr et al. found that the JAK inhibitor Ruxolitinib reduced the proliferation of human K-ras-mutated A549 cells transplanted into immunodeficient mice, and decreased the expression of tumor cell-derived pro-cancer factors IL-1β and IL-6. And studies have shown that JAK2 inhibitor TG101209 can inhibit T cell acute lymphoblastic leukemia (T-ALL) proliferation by inhibiting JAK/STAT pathway activation and regulating the interaction between apoptosis and autophagy.

28Inhibitors targeting STAT3, Danvatirsen, OPB-31121, OPB-51602, are in clinical trials in a variety of solid tumors, including colorectal cancer, non-small cell lung cancer, liver cancer, head and neck cancer, etc. Although still in Phase 1 trials, their feasibility for treating tumors is being further demonstrated. In addition, several inhibitors targeting the JAK/STAT pathway are being tested in multi-stage clinical trials in a variety of diseases, such as Momelitinib, Peficitinib, itacitinib, AZD1480, Fedratinib, Gandotinib, Filgotinib, Upadacitinib, Decernotinib, lestatitinib, Decernotinib, lestaurtinib, abrocitinib, ritlecitinib, brepocitinib, deucravacitinib, delgocitinib. The JAK/STAT pathway is activated in a variety of common solid tumors contributing to an aggressive phenotype. Studies also have shown that Ruxolitinib can regulate the expression of phosphorylated STAT1 in patients with STAT1 Gain-of-function mutations, thereby restoring the toxicity function of NK cells. Silibinin is a direct STAT3 targeting agent, which can not only reduce therapy-associated nephrotoxicity, neurotoxicity and cardiotoxicity in preclinical models but also has the potential to reverse cancer cell drug resistance. STAT3 inhibitor WP1066 also inhibited Treg and increased T cell toxicity in patients with melanoma brain metastasis.

6.2 Combination therapy with JAK/STAT inhibitors

29As we know, the clinical drug tolerance of some tumors is gradually emerging, so combined JAK/STAT inhibitor therapy may be a new treatment strategy (Table 3). JAK inhibitor (AZD1480) combined with EGFR inhibitor (cediranib) reduces tumor volume and microvascular density by reducing hypoxia and macrophage infiltration. Sun’s results showed that TG101209 increased radiosensitivity by inducing apoptosis and decreasing cell proliferation and vascular density in lung cancer. But in our experiments, we found that the JAK2 inhibitor, WP1066, combined with radiotherapy failed to reduce cell viability in gastric cell lines, which may be related to the cancer specificity. Matthew conducted a phase I/II trial to study the safety and efficacy of combining trastuzumab with ruxolitinib in patients with trastuzumab-resistant metastatic HER2+ breast cancer. However, the results did not observe an improvement in patient PFS. And Sukhmani found that momelotinib in combination with erlotinib did not appear to enhance the benefit of patients with EGFR-mutated NSCLC. Robert evaluated the JAKA1 inhibitor itacitinib in combination with corticosteroids or placebo for the treatment of acute GVHD, and the observed improvement in ORR at day 28 in the combination group did not reach the prespecified significance level. Filgotinib was found to improve signs and symptoms of rheumatoid arthritis, improve physical function, inhibit radiographic progression, and be well tolerated by RA patients with an inadequate response to methotrexate (MTX). Studies have shown that after combined treatment with the STAT3/5 inhibitor Static, the Oncolytic Adenovirus XVir-N-31 has increased viral replication and increased virus-induced death of bladder cancer cells. Furthermore, some clinical trials are ongoing. A phase II clinical trial investigated the efficacy and safety of adding the BCL-XL/BCL-2 inhibitor navitoclax in patients with myelofibrosis who progressed on ruxolitinib therapy or responded suboptimally to ruxolitinib monotherapy. The results demonstrated that patients achieved durable SVR35 (≥35% spleen volume reduction) and improved TSS50 (≥50% reduction in total symptom score).

30Moreover, potential natural products such as plant-derived cucurbitacin I and curcumin analogue ASC-J9 could be used as JAK/STAT inhibitors to treat related diseases, and the small molecule drugs, which screened from the databases, targeting JAK/STAT could also be regarded as treatment strategies for related diseases (various organ fibrosis, etc.).

7 Conclusion

31The JAK/STAT pathway, a key pathway for protein signaling on the membrane, is crucial in human cells. The dysregulation of this pathway has been considered one of the causes leading to disease progression and tumor growth. In tumors, JAK/STAT acts as a regulatory hub for transduction signals, which affects the activation of various inflammatory factors, growth factors, and angiogenic factors in the tumor microenvironment (TME), and participates in regulating the maturation, proliferation, and differentiation of various immune cells. In addition, JAK/STAT pathway is also affected by many extracellular mechanical signals and consequently mediates numerous downstream biological processes. Therefore, inhibition of this pathway has attracted widespread attention as a potential therapeutic strategy. Based on the underlying molecular and genomic mechanisms of JAK/STAT, the internal and external factors affecting JAK/STAT activity, epigenetic and transcription factors, and genetic causes of dysregulated JAK/STAT signaling, these provide good ideas for the development and implementation of targeted drugs. In order to properly incorporate JAK/STAT targeted drugs into multimodality therapies, including combinations with chemotherapy, radiotherapy, immunotherapy, and physiotherapy, we also need to find predictive biomarkers, not just the overactivation of pathways. In view of the different sensitivity of individuals to drugs, it will be a hot research direction for us to learn more about the changes in individual tumor genomes and help us make therapeutic regimens for different gene mutations in the future.

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IL-23-induced macrophage polarization and its pathological roles in mice with imiquimod-induced psoriasis · 2018
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90.
Hu J. Hu W. X. (2018 ). Targeting signaling pathways in multiple myeloma: Pathogenesis and implication for treatments. Cancer Lett. 414, 214–221.
Not in our library10.1016/j.canlet.2017.11.020
91.
Hu Z. Li Y. Yuan W. Jin L. Leung W. K. Zhang C. (2022 ). N6-methyladenosine of Socs1 modulates macrophage inflammatory response in different stiffness environments. Int. J. Biol. Sci. 18 (15), 5753–5769.
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Hunter A. M. Newman H. Dezern A. E. Steensma D. P. Niyongere S. Roboz G. J. (2021 ). Integrated human and murine clinical study establishes clinical efficacy of ruxolitinib in chronic myelomonocytic leukemia. Clin. Cancer Res. 27 (22), 6095–6105.
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Imada K. Bloom E. T. Nakajima H. Horvath-Arcidiacono J. A. Udy G. B. Davey H. W. (1998 ). Stat5b is essential for natural killer cell-mediated proliferation and cytolytic activity. J. Exp. Med. 188 (11), 2067–2074.
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Jakubzick C. Choi E. S. Carpenter K. J. Kunkel S. L. Evanoff H. Martinez F. J. (2004 ). Human pulmonary fibroblasts exhibit altered interleukin-4 and interleukin-13 receptor subunit expression in idiopathic interstitial pneumonia. Am. J. Pathol. 164 (6), 1989–2001.
Not in our library10.1016/s0002-9440(10)63759-5
95.
Jayaraman P. Parikh F. Lopez-Rivera E. Hailemichael Y. Clark A. Ma G. (2012 ). Tumor-expressed inducible nitric oxide synthase controls induction of functional myeloid-derived suppressor cells through modulation of vascular endothelial growth factor release. J. Immunol. 188 (11), 5365–5376.
Not in our library10.4049/jimmunol.1103553
96.
Jia H. Peng H. Hou Z. (2020 ). Ajuba: An emerging signal transducer in oncogenesis. Pharmacol. Res. 151, 104546.
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97.
Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition · 2020
No notice
98.
Jin Y. Ding L. Ding Z. Fu Y. Song Y. Jing Y. (2020 ). Tensile force-induced PDGF-BB/PDGFRβ signals in periodontal ligament fibroblasts activate JAK2/STAT3 for orthodontic tooth movement. Sci. Rep. 10 (1), 11269.
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99.
Johnson D. E. O'Keefe R. A. Grandis J. R. (2018 ). Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15 (4), 234–248.
Not in our library10.1038/nrclinonc.2018.8
100.
Jonchere B. Belanger A. Guette C. Barre B. Coqueret O. (2013 ). STAT3 as a new autophagy regulator. JAKSTAT 2 (3), e24353.
Not in our library10.4161/jkst.24353
101.
Jones L. L. Alli R. Li B. Geiger T. L. (2016 ). Differential T cell cytokine receptivity and not signal quality distinguishes IL-6 and IL-10 signaling during Th17 differentiation. J. Immunol. 196 (7), 2973–2985.
Not in our library10.4049/jimmunol.1402953
102.
Kearney M. Franks L. Lee S. Tiersten A. Makower D. F. Cigler T. (2021 ). Phase I/II trial of ruxolitinib in combination with trastuzumab in metastatic HER2 positive breast cancer. Breast Cancer Res. Treat. 189 (1), 177–185.
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103.
Kee B. L. Morman R. E. Sun M. (2020 ). Transcriptional regulation of natural killer cell development and maturation. Adv. Immunol. 146, 1–28.
Not in our library10.1016/bs.ai.2020.01.001
104.
Khanna D. Padilla C. Tsoi L. C. Nagaraja V. Khanna P. P. Tabib T. (2022 ). Tofacitinib blocks IFN-regulated biomarker genes in skin fibroblasts and keratinocytes in a systemic sclerosis trial. JCI Insight 7 (17), e159566.
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105.
Kirchmer M. N. Franco A. Albasanz-Puig A. Murray J. Yagi M. Gao L. (2014 ). Modulation of vascular smooth muscle cell phenotype by STAT-1 and STAT-3. Atherosclerosis 234 (1), 169–175.
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106.
Ko H. J. Kim Y. J. (2016 ). Signal transducer and activator of transcription proteins: Regulators of myeloid-derived suppressor cell-mediated immunosuppression in cancer. Arch. Pharm. Res. 39 (11), 1597–1608.
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107.
Kodama H. Fukuda K. Pan J. Makino S. Baba A. Hori S. (1997 ). Leukemia inhibitory factor, a potent cardiac hypertrophic cytokine, activates the JAK/STAT pathway in rat cardiomyocytes. Circ. Res. 81 (5), 656–663.
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108.
Komuro I. Kaida T. Shibazaki Y. Kurabayashi M. Katoh Y. Hoh E. (1990 ). Stretching cardiac myocytes stimulates protooncogene expression. J. Biol. Chem. 265 (7), 3595–3598.
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109.
Kong L. Y. Wei J. Sharma A. K. Barr J. Abou-Ghazal M. K. Fokt I. (2009 ). A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells. Cancer Immunol. Immunother. 58 (7), 1023–1032.
Not in our library10.1007/s00262-008-0618-y
110.
Kortylewski M. Kujawski M. Wang T. Wei S. Zhang S. Pilon-Thomas S. (2005 ). Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nat. Med. 11 (12), 1314–1321.
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111.
Kortylewski M. Xin H. Kujawski M. Lee H. Liu Y. Harris T. (2009 ). Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell 15 (2), 114–123.
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112.
Kroon P. Berry P. A. Stower M. J. Rodrigues G. Mann V. M. Simms M. (2013 ). JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. Cancer Res. 73 (16), 5288–5298.
Not in our library10.1158/0008-5472.can-13-0874
113.
Kujawski M. Kortylewski M. Lee H. Herrmann A. Kay H. Yu H. (2008 ). Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J. Clin. Invest. 118 (10), 3367–3377.
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Kunigal S. Lakka S. S. Sodadasu P. K. Estes N. Rao J. S. (2009 ). Stat3-siRNA induces Fas-mediated apoptosis in vitro and in vivo in breast cancer. Int. J. Oncol. 34 (5), 1209–1220.
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Kunisada K. Hirota H. Fujio Y. Matsui H. Tani Y. Yamauchi-Takihara K. (1996 ). Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. Circulation 94 (10), 2626–2632.
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Kunnen S. J. Malas T. B. Semeins C. M. Bakker A. D. Peters D. J. M. (2018 ). Comprehensive transcriptome analysis of fluid shear stress altered gene expression in renal epithelial cells. J. Cell Physiol. 233 (4), 3615–3628.
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117.
Kusmartsev S. Gabrilovich D. I. (2005 ). STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J. Immunol. 174 (8), 4880–4891.
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118.
La Manna S. De Benedictis I. Marasco D. (2021 ). Proteomimetics of natural regulators of JAK-STAT pathway: Novel therapeutic perspectives. Front. Mol. Biosci. 8, 792546.
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Lammerding J. Kamm R. D. Lee R. T. (2004 ). Mechanotransduction in cardiac myocytes. Ann. N. Y. Acad. Sci. 1015, 53–70.
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Langowski J. L. Zhang X. Wu L. Mattson J. D. Chen T. Smith K. (2006 ). IL-23 promotes tumour incidence and growth. Nature 442 (7101), 461–465.
Not in our library10.1038/nature04808
121.
Laouar Y. Welte T. Fu X. Y. Flavell R. A. (2003 ). STAT3 is required for Flt3L-dependent dendritic cell differentiation. Immunity 19 (6), 903–912.
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122.
Larmonier N. Marron M. Zeng Y. Cantrell J. Romanoski A. Sepassi M. (2007 ). Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. Cancer Immunol. Immunother. 56 (1), 48–59.
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123.
Lee B. Lee S. Lee Y. Park Y. Shim J. (2021 ). Emerin represses STAT3 signaling through nuclear membrane-based spatial control. Int. J. Mol. Sci. 22 (13), 6669.
Not in our library10.3390/ijms22136669
124.
Lee H. Herrmann A. Deng J. H. Kujawski M. Niu G. Li Z. (2009 ). Persistently activated Stat3 maintains constitutive NF-κB activity in tumors. Cancer Cell 15 (4), 283–293.
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125.
Lee K. H. Hsu E. C. Guh J. H. Yang H. C. Wang D. Kulp S. K. (2011 ). Targeting energy metabolic and oncogenic signaling pathways in triple-negative breast cancer by a novel adenosine monophosphate-activated protein kinase (AMPK) activator. J. Biol. Chem. 286 (45), 39247–39258.
Not in our library10.1074/jbc.m111.264598
126.
Levis M. Allebach J. Tse K. F. Zheng R. Baldwin B. R. Smith B. D. (2002 ). A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood 99 (11), 3885–3891.
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Li H. S. Yang C. Y. Nallaparaju K. C. Zhang H. Liu Y. J. Goldrath A. W. (2012 ). The signal transducers STAT5 and STAT3 control expression of Id2 and E2-2 during dendritic cell development. Blood 120 (22), 4363–4373.
Not in our library10.1182/blood-2012-07-441311
128.
Li J. (2013 ). JAK-STAT and bone metabolism. JAKSTAT 2 (3), e23930.
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129.
Liang H. Venema V. J. Wang X. Ju H. Venema R. C. Marrero M. B. (1999 ). Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth muscle cells. J. Biol. Chem. 274 (28), 19846–19851.
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130.
Liang X. Huang X. Zhou Y. Jin R. Li Q. (2016 ). Mechanical stretching promotes skin tissue regeneration via enhancing mesenchymal stem cell homing and transdifferentiation. Stem Cells Transl. Med. 5 (7), 960–969.
Not in our library10.5966/sctm.2015-0274
131.
Liang Z. W. Guo B. F. Li Y. Li X. J. Li X. Zhao L. J. (2011 ). Plasmid-based Stat3 siRNA delivered by hydroxyapatite nanoparticles suppresses mouse prostate tumour growth in vivo. Asian J. Androl. 13 (3), 481–486.
Not in our library10.1038/aja.2010.167
132.
Lin T. S. Mahajan S. Frank D. A. (2000 ). STAT signaling in the pathogenesis and treatment of leukemias. Oncogene 19 (21), 2496–2504.
Not in our library10.1038/sj.onc.1203486
133.
Little P. R. King V. L. Davis K. R. Cosgrove S. B. Stegemann M. R. (2015 ). A blinded, randomized clinical trial comparing the efficacy and safety of oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned dogs. Vet. Dermatol 26 (1), 23–30.
Not in our library10.1111/vde.12186
134.
The Role of JAK/STAT Pathway in Fibrotic Diseases: Molecular and Cellular Mechanisms · 2023
No notice
135.
Liu Y. Liu H. Meyer C. Li J. Nadalin S. Konigsrainer A. (2013 ). Transforming growth factor-beta (TGF-beta)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation. J. Biol. Chem. 288 (42), 30708–30719.
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136.
Liu Y. Wang L. Li S. Zhang T. Chen C. Hu J. (2022 ). Mechanical stimulation improves rotator cuff tendon-bone healing via activating IL-4/JAK/STAT signaling pathway mediated macrophage M2 polarization. J. Orthop. Transl. 37, 78–88.
Not in our library10.1016/j.jot.2022.08.008
137.
Signal Transducer and Activator of Transcription (STATs) Proteins in Cancer and Inflammation: Functions and Therapeutic Implication · 2019
No notice
138.
Luo J. Yu F. X. (2019 ). GPCR-hippo signaling in cancer. Cells 8 (5), 426.
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139.
Ma S. Meng Z. Chen R. Guan K. L. (2019 ). The hippo pathway: Biology and pathophysiology. Annu. Rev. Biochem. 88, 577–604.
Not in our library10.1146/annurev-biochem-013118-111829
140.
Machida T. Nishida K. Nasu Y. Nakahara R. Ozawa M. Harada R. (2017 ). Inhibitory effect of JAK inhibitor on mechanical stress-induced protease expression by human articular chondrocytes. Inflamm. Res. 66 (11), 999–1009.
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141.
Mankan A. K. Greten F. R. (2011 ). Inhibiting signal transducer and activator of transcription 3: Rationality and rationale design of inhibitors. Expert Opin. Investig. Drugs 20 (9), 1263–1275.
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Manokawinchoke J. Pavasant P. Limjeerajarus C. N. Limjeerajarus N. Osathanon T. Egusa H. (2021 ). Mechanical loading and the control of stem cell behavior. Arch. Oral Biol. 125, 105092.
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143.
Martinac B. Poole K. (2018 ). Mechanically activated ion channels. Int. J. Biochem. Cell Biol. 97, 104–107.
Not in our library10.1016/j.biocel.2018.02.011
144.
Mascarenhas J. Baer M. R. Kessler C. Hexner E. Tremblay D. Price L. (2019 ). Phase II trial of Lestaurtinib, a JAK2 inhibitor, in patients with myelofibrosis. Leuk. Lymphoma 60 (5), 1343–1345.
Not in our library10.1080/10428194.2018.1532509
145.
Matthews B. D. Thodeti C. K. Tytell J. D. Mammoto A. Overby D. R. Ingber D. E. (2010 ). Ultra-rapid activation of TRPV4 ion channels by mechanical forces applied to cell surface β1 integrins. Integr. Biol. (Camb) 2 (9), 435–442.
Not in our library10.1039/c0ib00034e
146.
McGlynn M. L. Schnitzler H. Shute R. Ruby B. Slivka D. (2021 ). The acute effects of exercise and temperature on regional mtDNA. Int. J. Environ. Res. Public Health 18 (12), 6382.
Not in our library10.3390/ijerph18126382
147.
Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis · 2022
No notice
148.
Mehta P. K. Griendling K. K. (2007 ). Angiotensin II cell signaling: Physiological and pathological effects in the cardiovascular system. Am. J. Physiol. Cell Physiol. 292 (1), C82–C97.
Not in our library10.1152/ajpcell.00287.2006
149.
Meng A. Anderson K. Nelson C. Ni L. Chuang S. M. Bellanti F. (2022 ). Exposure-response relationships for the efficacy and safety of filgotinib and its metabolite GS-829845 in subjects with rheumatoid arthritis based on phase 2 and phase 3 studies. Br. J. Clin. Pharmacol. 88 (7), 3211–3221.
Not in our library10.1111/bcp.15239
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Mesa R. Harrison C. Oh S. T. Gerds A. T. Gupta V. Catalano J. (2022 ). Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Leukemia 36 (9), 2261–2268.
Not in our library10.1038/s41375-022-01637-7
151.
On the origin of myeloid-derived suppressor cells · 2016
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152.
Mills C. D. Kincaid K. Alt J. M. Heilman M. J. Hill A. M. (2000 ). M-1/M-2 macrophages and the Th1/Th2 paradigm. J. Immunol. 164 (12), 6166–6173.
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153.
Mimura K. Teh J. L. Okayama H. Shiraishi K. Kua L. F. Koh V. (2018 ). PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 109 (1), 43–53.
Not in our library10.1111/cas.13424
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Mohrherr J. Haber M. Breitenecker K. Aigner P. Moritsch S. Voronin V. (2019 ). JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression. Int. J. Cancer 145 (12), 3376–3388.
Not in our library10.1002/ijc.32624
155.
Moskowitz A. J. Ghione P. Jacobsen E. Ruan J. Schatz J. H. Noor S. (2021 ). A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas. Blood 138 (26), 2828–2837.
Not in our library10.1182/blood.2021013379
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Movahedi K. Guilliams M. Van den Bossche J. Van den Bergh R. Gysemans C. Beschin A. (2008 ). Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood 111 (8), 4233–4244.
Not in our library10.1182/blood-2007-07-099226
157.
Mukherjee A. Tsuchiwata S. Nicholas T. Cook J. A. Modesto I. Su C. (2022 ). Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from phase II and phase III induction and maintenance studies. Clin. Pharmacol. Ther. 112 (1), 90–100.
Not in our library10.1002/cpt.2601
158.
Leptin-Induced JAK/STAT Signaling and Cancer Growth · 2016
No notice
159.
Muller R. (2019 ). JAK inhibitors in 2019, synthetic review in 10 points. Eur. J. Intern Med. 66, 9–17.
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160.
Murray P. J. (2007 ). The JAK-STAT signaling pathway: Input and output integration. J. Immunol. 178 (5), 2623–2629.
Not in our library10.4049/jimmunol.178.5.2623
161.
Naing A. Powderly J. D. Nemunaitis J. J. Luke J. J. Mansfield A. S. Messersmith W. A. (2022 ). Exploring the safety, effect on the tumor microenvironment, and efficacy of itacitinib in combination with epacadostat or parsaclisib in advanced solid tumors: a phase I study. J. Immunother. Cancer 10 (3), e004223.
Not in our library10.1136/jitc-2021-004223
162.
Najjar I. Deglesne P. A. Schischmanoff P. O. Fabre E. E. Boisson-Dupuis S. Nimmerjahn F. (2010 ). STAT1-dependent IgG cell-surface expression in a human B cell line derived from a STAT1-deficient patient. J. Leukoc. Biol. 87 (6), 1145–1152.
Not in our library10.1189/jlb.1109714
163.
Neradugomma N. K. Subramaniam D. Tawfik O. W. Goffin V. Kumar T. R. Jensen R. A. (2014 ). Prolactin signaling enhances colon cancer stemness by modulating Notch signaling in a Jak2-STAT3/ERK manner. Carcinogenesis 35 (4), 795–806.
Not in our library10.1093/carcin/bgt379
164.
Nguyen K. B. Salazar-Mather T. P. Dalod M. Y. Van Deusen J. B. Wei X. Q. Liew F. Y. (2002 ). Coordinated and distinct roles for IFN-αβ, IL-12, and IL-15 regulation of NK cell responses to viral infection. J. Immunol. 169 (8), 4279–4287.
Not in our library10.4049/jimmunol.169.8.4279
165.
Nishina T. Fujita T. Yoshizuka N. Sugibayashi K. Murayama K. Kuboki Y. (2022 ). Safety, tolerability, pharmacokinetics and preliminary antitumour activity of an antisense oligonucleotide targeting STAT3 (danvatirsen) as monotherapy and in combination with durvalumab in Japanese patients with advanced solid malignancies: A phase 1 study. BMJ Open 12 (10), e055718.
Not in our library10.1136/bmjopen-2021-055718
166.
Niu G. Wright K. L. Ma Y. Wright G. M. Huang M. Irby R. (2005 ). Role of Stat3 in regulating p53 expression and function. Mol. Cell Biol. 25 (17), 7432–7440.
Not in our library10.1128/mcb.25.17.7432-7440.2005
167.
Genetic partitioning of interleukin‐6 signalling in mice dissociates Stat3 from Smad3‐mediated lung fibrosis · 2012
No notice
168.
O'Shea J. J. Schwartz D. M. Villarino A. V. Gadina M. McInnes I. B. Laurence A. (2015 ). The JAK-STAT pathway: Impact on human disease and therapeutic intervention. Annu. Rev. Med. 66, 311–328.
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169.
Ogura M. Uchida T. Terui Y. Hayakawa F. Kobayashi Y. Taniwaki M. (2015 ). Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/refractory hematological malignancies. Cancer Sci. 106 (7), 896–901.
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Oh D. Y. Lee S. H. Han S. W. Kim M. J. Kim T. M. Kim T. Y. (2015 ). Phase I study of OPB-31121, an oral STAT3 inhibitor, in patients with advanced solid tumors. Cancer Res. Treat. 47 (4), 607–615.
Not in our library10.4143/crt.2014.249
171.
Olson M. R. Verdan F. F. Hufford M. M. Dent A. L. Kaplan M. H. (2016 ). STAT3 impairs STAT5 activation in the development of IL-9-secreting T cells. J. Immunol. 196 (8), 3297–3304.
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172.
Ostrand-Rosenberg S. Grusby M. J. Clements V. K. (2000 ). Cutting edge: STAT6-deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma. J. Immunol. 165 (11), 6015–6019.
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173.
Padda S. K. Reckamp K. L. Koczywas M. Neal J. W. Kawashima J. Kong S. (2022 ). A phase 1b study of erlotinib and momelotinib for the treatment of EGFR-mutated, tyrosine kinase inhibitor-naive metastatic non-small cell lung cancer. Cancer Chemother. Pharmacol. 89 (1), 105–115.
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174.
Pail G. Huf W. Pjrek E. Winkler D. Willeit M. Praschak-Rieder N. (2011 ). Bright-light therapy in the treatment of mood disorders. Neuropsychobiology 64 (3), 152–162.
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175.
Pan J. Fukuda K. Kodama H. Makino S. Takahashi T. Sano M. (1997 ). Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. Circ. Res. 81 (4), 611–617.
Not in our library10.1161/01.res.81.4.611
176.
Pan J. Fukuda K. Saito M. Matsuzaki J. Kodama H. Sano M. (1999 ). Mechanical stretch activates the JAK/STAT pathway in rat cardiomyocytes. Circ. Res. 84 (10), 1127–1136.
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177.
Park C. Li S. Cha E. Schindler C. (2000 ). Immune response in Stat2 knockout mice. Immunity 13 (6), 795–804.
Not in our library10.1016/s1074-7613(00)00077-7
178.
Park S. J. Nakagawa T. Kitamura H. Atsumi T. Kamon H. Sawa S. (2004 ). IL-6 regulates in vivo dendritic cell differentiation through STAT3 activation. J. Immunol. 173 (6), 3844–3854.
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179.
Patel M. R. Dash A. Jacobson B. A. Ji Y. Baumann D. Ismail K. (2019 ). JAK/STAT inhibition with ruxolitinib enhances oncolytic virotherapy in non-small cell lung cancer models. Cancer Gene Ther. 26 (11-12), 411–418.
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180.
Paukku K. Valgeirsdottir S. Saharinen P. Bergman M. Heldin C. H. Silvennoinen O. (2000 ). Platelet-derived growth factor (PDGF)-induced activation of signal transducer and activator of transcription (Stat) 5 is mediated by PDGF beta-receptor and is not dependent on c-src, fyn, jak1 or jak2 kinases. Biochem. J. 345 Pt 3, 759–766.
Not in our library10.1042/bj3450759
181.
Peeva E. Guttman-Yassky E. Banerjee A. Sinclair R. Cox L. A. Zhu L. (2022 ). Maintenance, withdrawal, and re-treatment with ritlecitinib and brepocitinib in patients with alopecia areata in a single-blind extension of a phase 2a randomized clinical trial. J. Am. Acad. Dermatol 87 (2), 390–393.
Not in our library10.1016/j.jaad.2021.12.008
182.
Peterson W. M. Wang Q. Tzekova R. Wiegand S. J. (2000 ). Ciliary neurotrophic factor and stress stimuli activate the Jak-STAT pathway in retinal neurons and glia. J. Neurosci. 20 (11), 4081–4090.
Not in our library10.1523/jneurosci.20-11-04081.2000
183.
Plimack E. R. Lorusso P. M. McCoon P. Tang W. Krebs A. D. Curt G. (2013 ). AZD1480: a phase I study of a novel JAK2 inhibitor in solid tumors. Oncologist 18 (7), 819–820.
Not in our library10.1634/theoncologist.2013-0198
184.
Ploscariu N. Kuczera K. Malek K. E. Wawrzyniuk M. Dey A. Szoszkiewicz R. (2014 ). Single molecule studies of force-induced S2 site exposure in the mammalian Notch negative regulatory domain. J. Phys. Chem. B 118 (18), 4761–4770.
Not in our library10.1021/jp5004825
185.
Qin Q. Yang H. Zhang C. Han X. Guo J. Fan Z. (2021 ). lncRNA HHIP-AS1 promotes the osteogenic differentiation potential and inhibits the migration ability of periodontal ligament stem cells. Stem Cells Int. 2021, 1–12.
Not in our library10.1155/2021/5595580
186.
Quesnelle K. M. Boehm A. L. Grandis J. R. (2007 ). STAT-mediated EGFR signaling in cancer. J. Cell Biochem. 102 (2), 311–319.
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190.
STAT3 antisense oligonucleotide AZD9150 in a subset of patients with heavily pretreated lymphoma: results of a phase 1b trial · 2018
No notice
191.
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213.
STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. · 2011
Not checked
214.
Song Z. Xiong B. Zheng H. Manyande A. Guan X. Cao F. (2017 ). STAT1 as a downstream mediator of ERK signaling contributes to bone cancer pain by regulating MHC II expression in spinal microglia. Brain Behav. Immun. 60, 161–173.
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220.
IFN-γ is required for cytotoxic T cell-dependent cancer genome immunoediting · 2017
Corrected
221.
Patient- and physician-reported outcomes from two phase 3 randomized studies (RAJ3 and RAJ4) of peficitinib (ASP015K) in Asian patients with rheumatoid arthritis · 2021
Not checked
222.
Teng Y. Ross J. L. Cowell J. K. (2014 ). The involvement of JAK-STAT3 in cell motility, invasion, and metastasis. JAKSTAT 3 (1), e28086.
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225.
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244.
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248.
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252.
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Wu L. Deng Z. Peng Y. Han L. Liu J. Wang L. (2017 ). Ascites-derived IL-6 and IL-10 synergistically expand CD14(+)HLA-DR(-/low) myeloid-derived suppressor cells in ovarian cancer patients. Oncotarget 8 (44), 76843–76856.
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254.
Xiao J. Gong Y. Chen Y. Yu D. Wang X. Zhang X. (2017 ). IL-6 promotes epithelial-to-mesenchymal transition of human peritoneal mesothelial cells possibly through the JAK2/STAT3 signaling pathway. Am. J. Physiol. Ren. Physiol. 313 (2), F310–F318.
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255.
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256.
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257.
Yahata Y. Shirakata Y. Tokumaru S. Yamasaki K. Sayama K. Hanakawa Y. (2003 ). Nuclear translocation of phosphorylated STAT3 is essential for vascular endothelial growth factor-induced human dermal microvascular endothelial cell migration and tube formation. J. Biol. Chem. 278 (41), 40026–40031.
Not in our library10.1074/jbc.m301866200
258.
Yang J. Liao D. Chen C. Liu Y. Chuang T. H. Xiang R. (2013 ). Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells 31 (2), 248–258.
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259.
Mitochondrial Ca2+ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function · 2015
Not checked
260.
Yin Q. Wolkerstorfer A. Lapid O. Niessen F. B. Van Zuijlen P. P. M. Gibbs S. (2023 ). The JAK-STAT pathway in keloid pathogenesis A systematic review with qualitative synthesis. Exp. Dermatol.
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Yu H. Kortylewski M. Pardoll D. (2007 ). Crosstalk between cancer and immune cells: Role of STAT3 in the tumour microenvironment. Nat. Rev. Immunol. 7 (1), 41–51.
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Yu H. Pardoll D. Jove R. (2009 ). STATs in cancer inflammation and immunity: A leading role for STAT3. Nat. Rev. Cancer 9 (11), 798–809.
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Yu J. Wang Y. Yan F. Zhang P. Li H. Zhao H. (2014 ). Noncanonical NF-κB activation mediates STAT3-stimulated Ido upregulation in myeloid-derived suppressor cells in breast cancer. J. Immunol. 193 (5), 2574–2586.
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264.
Zeiser R. Socie G. Schroeder M. A. Abhyankar S. Vaz C. P. Kwon M. (2022 ). 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. 9 (1), e14–e25.
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265.
Zhang J. Wei X. Zhang W. Wang F. Li Q. (2020a ). MiR-326 targets MDK to regulate the progression of cardiac hypertrophy through blocking JAK/STAT and MAPK signaling pathways. Eur. J. Pharmacol. 872, 172941.
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266.
Zhang J. Z. Lu T. W. Stolerman L. M. Tenner B. Yang J. R. Zhang J. F. (2020b ). Phase separation of a PKA regulatory subunit controls cAMP compartmentation and oncogenic signaling. Cell 182 (6), 1531–1544.e15.
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267.
Zhang Q. Zhang C. He J. Guo Q. Hu D. Yang X. (2015 ). STAT3 inhibitor stattic enhances radiosensitivity in esophageal squamous cell carcinoma. Tumour Biol. 36 (3), 2135–2142.
Not in our library10.1007/s13277-014-2823-y
268.
Zhang T. Ma J. Cao X. (2003 ). Grb2 regulates Stat3 activation negatively in epidermal growth factor signalling. Biochem. J. 376 (2), 457–464.
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269.
IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma · 2020
No notice
270.
Zhu S. Liu M. Bennett S. Wang Z. Pfleger K. D. G. Xu J. (2021 ). The molecular structure and role of CCL2 (MCP-1) and C-C chemokine receptor CCR2 in skeletal biology and diseases. J. Cell Physiol. 236 (10), 7211–7222.
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271.
Zhu S. Phatarpekar P. V. Denman C. J. Senyukov V. V. Somanchi S. S. Nguyen-Jackson H. T. (2014 ). Transcription of the activating receptor NKG2D in natural killer cells is regulated by STAT3 tyrosine phosphorylation. Blood 124 (3), 403–411.
Not in our library10.1182/blood-2013-05-499707
272.
Zorn E. Nelson E. A. Mohseni M. Porcheray F. Kim H. Litsa D. (2006 ). IL-2 regulates FOXP3 expression in human CD4+CD25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108 (5), 1571–1579.
Not in our library10.1182/blood-2006-02-004747

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