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The Role of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Metabolism

Ling-Yu Tian, Daniel J. Smit, Manfred Jücker

International Journal of Molecular Sciences · 2023 · Review · CC BY

doi:10.3390/ijms24032652

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the world. Metabolic reprogramming is considered a new hallmark of cancer, but it remains unclearly described in HCC. The dysregulation of the PI3K/AKT/mTOR signaling pathway is common in HCC and is, therefore, a topic of further research and the concern of developing a novel target for liver cancer therapy. In this review, we illustrate mechanisms by which this signaling network is accountable for regulating HCC cellular metabolism, including glucose metabolism, lipid metabolism, amino acid metabolism, pyrimidine metabolism, and oxidative metabolism, and summarize the ongoing clinical trials based on the inhibition of the PI3K/AKT/mTOR pathway in HCC.

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

Primary liver cancer (PLC) is one of the leading causes of cancer mortality worldwide, with around 841,000 new cases and 781,000 deaths every year. About 80% of all PLC are hepatocellular carcinomas (HCC), with increasing incidences over the past few years, making HCC the second leading cause of cancer death in East Asia and the sixth leading cause of cancer death in Western countries. The main risk factors of HCC include hepatitis virus infection, auto-immune diseases, drug and non-drug related toxicity, as well as non-alcohol fatty liver disease (NAFLD). Increasing evidence demonstrates the close connection between metabolic factors, including metabolic syndrome, and the HCC prevalence in NAFLD patients. Metabolic reprogramming is the significant metabolic phenotype of tumors. Several metabolic enzymes, involved in glycolysis, lipogenesis, amino acid synthesis, and nucleotide biosynthesis, are augmented to reinforce the anabolic development of tumors in the process of metabolic reprogramming. Malignant tumors can alter their metabolic pathways to sustain the high energy demand for uncontrolled growth and proliferation. The Warburg effect is one of the most observed metabolic changes in malignancy that includes abnormally high glycolysis activity followed by lactate fermentation even in the presence of oxygen.

Oncogenic signaling transduction pathways, including the phosphoinositide 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR) pathways, enhance the Warburg effect in tumors, facilitating cancer cell growth and metastasis. The liver plays an important role as a metabolic organ in the maintenance of body metabolic homeostasis and has crucial functions in regulating various metabolic pathways. Cancer with activated PI3K/AKT signaling has been revealed to become more aggressive, and AKT pathway activation has been shown as a notable risk factor for earlier recurrence and poor prognosis in liver cancer patients. Proteins of the PI3K/AKT/mTOR signaling pathway are significantly raised in PET/CT-positive HCC patients, indicating that activation of this pathway might be a key factor of the glycolytic phenotype in HCC cells. Some mTOR inhibitors have been tested for treatment of HCC but have failed in clinical trials, and several new inhibitors on the PI3K/AKT/mTOR pathway are now in clinical trials for HCC patients. However, the knowledge on the interplay of PI3K/AKT/mTOR signaling and its metabolic role in HCC is still limited.

In this review, we highlight the role of the PI3K/AKT/mTOR pathway for the metabolism of HCC, with special emphasis on the molecular interactions. In addition, we offer an update on the ongoing clinical trials targeting the PI3K/AKT/mTOR pathway for HCC therapy.

2. The PI3K/AKT/mTOR Pathway in HCC

The PI3K/AKT/mTOR signaling pathway regulates crucial cellular processes in the physiological setting as well as most hallmarks of cancer, including cell cycle, survival, metabolism, motility, and angiogenesis. Dysregulation of the phosphatidylinositol 3-kinase (PI3K) is one of the most frequent events in tumorigenesis. Currently, three classes of PI3K are known in the human genome, i.e., class I, class II, and class III. The Class I PI3K are mainly known to drive tumorigenesis, and the activated Class I PI3K phosphorylates the phosphatidylinositol 4,5- biphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). The Class I PI3Ks include four catalytic units encoded by PIK3CA, PIK3CB, PIK3CG, and PIK3CD. In general, mutation of PI3K catalytic isoform p110α is the most common in human cancers, while the catalytic isoforms p110β, p110δ, and p110γ are rarely mutated but can be overexpressed in cancer.

PI3K is especially highly expressed in HCC tumor tissue, and the upregulation of PIK3CA was associated with HCC proliferation and negatively correlated with apoptosis. In addition, high expression of PIK3CA was associated with an unfavorable prognosis in HCC patients. HCC patients with an early-stage recurrence have a higher mutation rate of PIK3CB. Previous research demonstrated that certain microRNAs, including miR-142-3p, repress HCC progression and increase apoptosis to inhibit HCC by decreasing the PIK3CG-mediated activation of the PI3K/AKT pathway. Regarding MiR-7, which targets PIK3C, it has been demonstrated that it controls cell proliferation and metastasis through the PI3K/AKT/mTOR pathway in HCC.

There are three Class II PI3K isoforms (PI3K-C2α, PI3K-C2β, and PI3K-C2γ) with different roles. PI3K-C2α plays a prominent role in endocytosis, vesicular trafficking, and mitosis; PI3K-C2β is related to cell migration and mTOR signaling repression and PI3K-C2γ regulates AKT2 activation and glycogen storage. Downregulation of PI3KC2α leads to degraded vascular endothelial growth factor A (VEGFA)-mediated signaling and decreased angiogenesis in human HCC cells. PI3K-C2β plays a crucial role in hepatitis C virus (HCV) propagation in human hepatocellular carcinoma cells.

Class III PI3K (i.e., PIK3C3) plays an essential role in cellular processes. Inhibition of PIK3C3 blocks the activation of SGK3, which is the cancer stem cell (CSCs) promoter, and AMP-activated kinase (AMPK), thereby repressing the growth of HCC CSCs in mice. The serine and threonine kinase AKT family includes three isoforms (i.e., AKT1, AKT2, and AKT3). A wide range of diseases, including cancer, is caused by AKT dysregulation. In hepatocytes, expression of AKT1 as well as AKT2, but not AKT3, can be detected. It has been demonstrated that c-MYC activation is strongly correlated with phosphorylated AKT1 expression and that HCC patients with relatively higher expression of AKT1, but not AKT2, have an unfavorable outcome. However, previous research reported that AKT2 impacts the prognosis of HCC patients and that AKT2 may promote cell proliferation and invasion. Furthermore, Galicia et al. reported that PI3K/AKT signaling is activated by loss of the tumor suppressor phosphatase and tensin homolog (PTEN). The preliminary role of AKT2 in the context of tumor transformation is not for the pro-survival or pro-growth of tumor cells; however, it displays the crucial function of metabolic regulation in the HCC model of mice.

The mammalian target of rapamycin (mTOR) kinase is a proficient regulator of protein synthesis that connects nutrient sensing to cell growth and is frequently observed in cancer. The different proteins binding to mTOR activate their function by forming two complexes, which are called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Activation of PI3K and AKT leads to mTORC1 activation and phosphorylation of ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein-1 (4E-BP1). The mTORC2 complex includes the rapamycin-insensitive companion of mTOR (Rictor) and phosphorylates AKT, promoting AKT kinase activity. Constitutive activation of PI3K/AKT/mTOR has been reported in cancer. In 50% of HCC cases, an upregulation of the mTOR pathway has been reported, which underlines the role of mTORC1 as a potential therapeutic target. However, the long-term usage of the inhibitors of mTORC1 increases interleukin-6 (IL-6) production, activates the signal transducer and activator of transcription 3 (STAT3), and facilitates HCC development in a murine obesity liver model. For mTORC2, it has been pointed out that hepatic mTORC2 facilitates hepatosteatosis and cancer via de novo fatty acid and lipid synthesis in HCC.

3.1. Glucose Metabolism in HCC

Increased aerobic glycolysis is a crucial hallmark of cancer metabolism. Inhibition of the AKT/mTOR signaling pathway decreases the aerobic glycolysis in HCC cells, thereby eventually abolishing their cell growth. It has been reported that liver cancer is often driven by the activation of AKT/mTOR signaling and that glycolysis activity is increased during HCC growth. Therefore, the suppression of AKT/mTORC1 might be a suitable strategy to prevent HCC development. However, mitochondrial glucose oxidation that occurred in HCC cell metabolism independently of the PI3K/AKT/mTOR pathway has also been revealed previously. In HCC cell lines, the Warburg effect is elevated with increasing glucose uptake, and it is revealed that miR-873 activates the key glycolytic proteins AKT/mTOR via targeting Nedd4 family-interacting protein 1 (NDFIP1), which initiates metabolic change and causes hepatocellular carcinoma formation and metastasis. Laminin subunit gamma 1 (Lamc 1) decreased the growth of HCC cells by promoting tumor cell death and decreased glucose transportation via the inhibition of expression of pyruvate kinase M2 (PKM2), mechanically reducing the expression of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA), which implied that the AKT pathway plays a crucial role in the progression of HCC by transforming glucose metabolism. Furthermore, the mTOR kinase is an essential downstream effector of AKT, and activation of mTOR hampers its downstream effector, eIF4E binding protein (4EBP1). This is stimulating the initiation of protein translation, thereby resulting in increased glucose transporter 1 (GLUT1) translocation and hexokinase 2 (HK2) activity, ultimately enhancing glucose uptake and glycolysis. Cui et al. found that inhibitors of AKT and mTOR repressed the motility of liver cancer cells, decreased glucose consumption and lactate production, and hindered HK2 expression, suggesting that inhibition of the AKT/mTOR signaling axis deterred cell motility by repressing glycolysis in HCC cells. Moreover, lower AKT activity results in cell cycle arrest and decreased metabolic flux to glycolysis and the tricarboxylic acid (TCA) cycle to repress tumor growth.

Glucose is catabolized by two parallel metabolic pathways, i.e., glycolysis and the pentose phosphate pathway (PPP). Glucose flux through the glycolytic pathway can be shifted to the pentose phosphate pathway (PPP). The PPP (also known as the phosphogluconate pathway or the hexose monophosphate shunt) branched from glycolysis at the first step of glucose-6-phosphate (G-6-P). The PPP plays an important role in cancer cell proliferation and growth. 6-phosphogluconate dehydrogenase (6PGD), a key enzyme within the PPP, has been demonstrated to contribute to oncogenesis. Activation of the PI3K/AKT signaling pathway leads to higher G6PD activity, thereby enhancing metabolic activities and promoting cancer cell growth. G6PD overexpression promotes growth in normal liver cells, whereas targeting G6PD decreases HCC growth and HCC cell survival. Cheng et al. reported that there was an essential reciprocal crosstalk between the PI3K/AKT signal and PPP metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the E3 ligase tripartite motif-containing protein 21 (TIRM21) and promotes the PPP, which in turn supports AKT activation and additionally enables cancer metabolic reprogramming by suppressing the expression of the AKT inactivator pleckstrin homology-like domain family A member 3 (PHLDA3). VersicanV1, which is the protein of the extracellular matrix, could promote the Warburg effect of HCC cells through the epidermal growth factor receptor (EGFR)–PI3K–AKT signaling pathway, consequently increasing the proliferation, invasion, and metastasis of HCC cells. Furthermore, cluster of differentiation 36 (CD36), an integral transmembrane glycoprotein, prompted mTOR-mediated oncogenic glycolysis via activation of the PI3K/AKT signaling axis in HCC (Figure 1).

Lactate accumulation in cancer—a hallmark of the Warburg effect—has recently been demonstrated to control cancer cell metabolism and survival. Kirk et al. have reported that CD147 plays a pivotal role in lactate transport, indicating that CD147 initiates the activation of the PI3K/AKT signaling axis, hence controlling lactate export in liver cancer cells (Figure 1). A prior investigation has also described a correlation between lactic acidosis and activity of the PI3K/AKT pathway in cancer cells (Figure 1).

3.2. Lipid Metabolism in HCC

Lipid metabolism has been implicated in tumorigenesis as an essential energy supplier, sustaining cell growth, and delivering the intermediate substances for biosynthesis in the cancer cells. It has been previously reported that fatty acids and cholesterol are crucial for the growth and progression of tumors, as they are the elements of the cell membrane. The liver is an essential organ for energy metabolism, lipid biogenesis, as well as the distribution of lipids. An anomalous lipid metabolism was observed in liver cancer cells generated by hydrodynamic injection of activated forms of AKT and Nras via a transposon system into mouse hepatocytes. The activation of the AKT/mTOR signaling pathway downstream of transmembrane glycoprotein CD147 triggers the transcription of key fatty acid-related genes, including the fatty acid synthase and acetyl-CoA-carboxylase (ACC), to facilitate the fatty acid synthesis in HCC cells. The AKT/mTOR/SREBP-1 (Sterol regulatory-element binding protein 1) signaling pathway is a key pathway to regulate hepatic cellular lipid metabolism. In HCC cell lines, the inhibition of AKT targets lipogenesis in the HepG2 cancer cell line. Sterol regulatory-element binding proteins (SREBPs) are transcription factors that regulate the expression of genes involved in lipid synthesis. Furthermore, the AKT/mTORC1/S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that include inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Furthermore, suppression of the adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines, and AKT-dependent cell proliferation. AKT/mTOR/SREBP signaling by insulin and growth factors is the preliminary axis in anabolic metabolism, which assembles substances related to the tumor. In addition, it was shown that activation of the AKT/mTOR signaling pathway upregulates SREBP1 expression, which enhances lipid metabolism by activating gene transcription of lipogenesis, thereby promoting the growth of HCC cells. The fatty acid synthase (FASN) is essential for AKT-mediated carcinogenesis of HCC. While the dependency on the FASN was demonstrated in HCC, it could not be shown for cholangiocarcinoma. Celecoxib, a non-steroidal anti-inflammatory drug, targets the cyclooxygenase 2 (COX-2)/AKT pathway and was sufficient to inhibit the progress of HCC by inhibiting lipogenesis. Within the hypoxic tumor microenvironment, the activated AKT/mTOR pathway causes lipogenesis and lipid accumulation during HCC progression and leads to proliferation, increased viability, and angiogenesis. In non-transformed and non-proliferative hepatocytes, nuclear factor erythroid 2-related factor 2 (NRF2) directly triggers transcription of growth factor genes encoding the platelet-derived growth factor receptors ligand platelet-derived growth factor C and the EGFR ligands transforming growth factor alpha and amphiregulin, which contribute to AKT activation via autocrine signaling to control hepatic glucose and lipid metabolism (Figure 2).

3.3. Amino Acid Metabolism in HCC

Glutamine is one of the most common amino acids. Rapidly proliferating cells, such as immune cells, as well as cancer cells, have a high demand for glutamine. Cancer cells increase their rate of glucose and glutamine metabolism for bioenergetic and anabolic intents, in which a substantial amount of external carbon sources are redirected to produce DNA, proteins, and lipids that are required for proliferation. Activation of PI3K/AKT signaling leads to glutamine utilization in the metabolic pathways to promote proliferation. Glutamine can activate mTORC1 through the mTOR signal pathway by Rag GTPase-dependent and -independent mechanisms. Liver cancer bears a metabolic dependency on glutamine, and exploiting metabolic vulnerabilities may be a promising target for the treatment of liver cancer. The glutaminase 1 (GLS1), the key enzyme in glutamine metabolism, is highly expressed in HCC tissue compared to healthy liver tissue. Furthermore, GLS1 was previously correlated with clinicopathological features and a poorer prognosis in HCC patients. The potential mechanism is that GLS1 activates the AKT pathway to promote the proliferation of HCC. Hepatocellular carcinoma tumorigenesis is facilitated by glutamine metabolism through the activation of a positive feedback loop involving the mTORC2/AKT/C-MYC axis. Subsequent upregulation of glutamine synthetase (GS) expression and mTORC1 signaling ultimately release the influence of sirtuin4 (SIRT4) on glutamate dehydrogenase (GDH). N-Myc downstream-regulated gene 2(NDRG2)-dependent inhibition of c-Myc via the PI3K/AKT pathway can further suppress glutaminolysis in tumor cells. Amino acid-deficient diets and disruption of arginine metabolism have been shown to be a potential nutritive treatment for tumor patients, including HCC patients. The previous results from Saha et al. showed that tumors with basal PI3K/AKT activity should be sensitive to amino acid deprivation; however, those with high PI3K/AKT pathway activity should be resistant. Amino acid deprivation could still induce quiescence in normal cells, accordingly setting up the proliferating cancer cells to be more sensitively affected by drugs that target tumor cells. The use of glutamine is important; however, the higher glutamine concentrations may also cause the formation of other metabolic substances, including amino acids, which help the liver to grow. Furthermore, NAD(P)H quinone dehydrogenase 1 (Nqo1) ablation-initiated suppression of the PI3K/AKT pathway, repressed the expression of glutaminolysis-related genes, and drove metabolic adaptation in hepatocytes. Contrarily, Nqo1 overexpression induced hyperactivation of the PI3K/AKT signaling axis and increased the metabolic adaptation rate (Figure 3). Interestingly, based on the metabolism-related gene used to stratify the HCC patients, the patients in the group with the PI3K/AKT/mTOR signaling pathway show the activation of asparagine synthetase (ASNS), glycolysis, and the pentose phosphate pathway.

3.4. Pyrimidine Metabolism in HCC

In addition to protein and lipid synthesis, pyrimidine synthesis represents another major anabolic process that is responsible for cellular growth regulation. The nucleotide metabolism is an essential metabolic process that creates purine and pyrimidine for cell proliferation, and a raised nucleotide metabolism sustains the disordered growth of tumors, which is a hallmark of cancer.

Growing evidence shows that pyrimidine metabolism can increase tumor malignancy in cells. The expression of key enzymes of the pyrimidine metabolism can predict the prognosis of HCC patients. The ubiquitin-conjugating enzyme E2T (UBE2T) increases the expression of the de novo synthesis of pyrimidine metabolism associated enzymes, including carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase (CAD), dihydroorotate dehydrogenase (DHODH), and uridine 5′-monophosphate synthase (UMPS), and enhances the pyrimidine metabolism by facilitating AKT ubiquitination and AKT/β-catenin signaling, thereby promoting the HCC progression. Increased purinergic signaling regulated by PI3K pathway-dependent activation of E2F transcription factor 1 (E2F1) mediated by the cyclin D-cyclin-dependent kinase 4/6 complex facilitates HCC tumorigenesis, indicating the possibility of targeting purine metabolic reprogramming as a potential treatment for patients with HCC. Fu et al. have indicated that the vasoactive intestinal polypeptide type-I receptor (VIPR1) is decreased in HCC and that VIPR1 inhibits HCC growth by regulating the phosphorylation of the mTOR pathway as well as pyrimidine biosynthesis. Moreover, mTORC1 plays a key role in controlling cell biosynthesis and growth, and mTOC1 activation following PI3K/AKT signaling results in the S6K1-mediated phosphorylation of CAD. CAD, in turn, facilitates the pyrimidine de novo pathway flux and elevates pyrimidine synthesis (Figure 4).

3.5. Oxidative Metabolism in HCC

Reactive oxygen species (ROS) are a set of favorably reactive small molecules. The balance of ROS is essential for cell fate, which maintains cell proliferation, differentiation, and promotes cancer metastasis. ROS is positively correlated with DNA damage and the differentiation grade of HCC. Previous research has revealed an interaction between the ROS and AKT signaling pathway. Zhao et al. discovered that cancer stem-like sphere cells derived from the human HCC cell line HepG2 may differentiate into endothelial cells by activation of AKT. Thus, targeting the ROS-dependent AKT signal axis may represent a method for human HCC treatment. For the patients with HCC recurrence after liver transplantation (LT), ischemia–reperfusion injury (IRI) is an inescapable outcome after LT, particularly in the early stage, and the investigations have shown that IRI potentially raises the risk of HCC recurrence after LT. Hepatic IRI is intensively related to the presence of ROS in hepatocytes, and a high level of ROS can activate AKT signaling in HCC cell lines. The activation of AKT is caused by ROS production in HCC cell lines, which is consistent with previous observations. The accumulation of ROS is also related to autophagy and apoptosis and impacts the cell cycle regulation of transformed hepatocytes in HCC, as ROS can act as upstream factors to regulate the AKT/mTOR pathway. Similarly, it has been described that the AKT signaling pathway was activated upon ROS generation in the Huh7, HepG2, and BEL7402 human HCC cell lines. In hepatitis B virus (HBV)-related HCC, the HBV plays an important role in HCC formation. The X protein (HBx) coded by the HBV genome is the key regulatory protein in HCC progression. The HBx-induced ROS stimulates the AKT pathway via oxidative inactivation of PTEN, while HBx and ROS preserve a positive regulatory loop, which exacerbates hepatocellular tumorigenesis via cyclin D1. Furthermore, the ROS-activated AKT is involved in telomere maintenance via H2O2-mediated AKT activity. Targeting the telomerase activity, which is critical in HCC, by reducing ROS levels through an antioxidant agent or by down-regulating p-AKT levels may become a therapeutic target for HCC patients. Ren et al. have shown that the mitochondrial Ca2+ uptake mediated by mitochondrial calcium uniporter regulator 1 (MCUR1) plays a crucial part in the regulation of HCC cell survival by raising ROS production via regulating AKT and p53 (Figure 5). Meanwhile, activation of ROS/AKT signaling has been associated with HCC cell growth and metastasis.

4. Metabolic Reprogramming in the HCC Tumor Microenvironment

The tumor microenvironment (TME) is a critical contributor to HCC cell growth, invasion, and metastasis. Immune cells, as an essential part of the TME, including expanded infiltrations of T cells and NK cells, are favorable prognostic indicators, emphasizing the prospects of immunotherapy in HCC treatment. Meanwhile, there is growing evidence that the metabolism of cell types in the TME, like immune cells, can modulate tumor progression. Nevertheless, a vicious competition potential exists between tumor cells and immune cells in the tumor microenvironment, and metabolic competition cannot only influence the growth of tumor cells, but can also lead to a loss of immune cell functions due to the lack of nutrition in the microenvironment.

Macrophages have been associated with tumor progression and resistance to treatment by delivering malignant cells with nutritional supplements. Lactic acid, created by cancer cells as a product of glycolysis, has an essential function in signaling transduction, contributing to the M2-like polarization of tumor-associated macrophages. In tumors, like HCC, the polarization of the macrophages may be caused by the increased lactic acid concentration in the tumor microenvironment, regulating the macrophage polarization through the AKT pathway. However, it has been demonstrated that M1 polarized macrophages have improved glycolytic metabolism and damaged oxidative phosphorylation through the AKT/mTOR/HIF-1α signaling axis. These results underline the importance of the AKT signaling pathway in the M1/M2 polarization of macrophages for HCC.

The consensus opinion of AKT is that it has a universal function in regulating T cell metabolism, but evidence for AKT-independent pathways that regulate T cell metabolism, survival, and proliferation has now been demonstrated. A previous study reported that AKT determines the T cell fates but is not important for regulation of the T cell metabolism. However, the inhibition of the AKT pathway suppresses fatty acid oxidation and enhances the mitochondrial spare respiratory capacity in tumor infiltrating T cells.

AKT activation relies on lipid oxidation and short-chain fatty acids instead of glucose or glycolysis in human T regulatory (Treg) cells. The increasing fractions of Treg cells contribute to intrahepatic metastasis of HCC, as Treg cells are one of the immune-inhibition factors that comply with immune repression during the immune effector functions. Programmed death ligand 1(PD-L1) as the immune checkpoint effects the Treg cells by inhibition of the AKT/mTOR/S6 signaling pathway, and enriching PTEN. PD-1/PD-L1 interaction may block mTOR signaling by AKT and PI3K inhibition, thereby decreasing the glycolysis rate of T-infiltrating cells in human HCC. Immunometabolism, which is the metabolic reprogramming after the activation of the immune cells, depends on the crosstalk between PI3K/AKT/mTOR and the LKB1/AMPK (liver kinase B1/AMP-activated protein kinase) signaling pathway, which is critical for regulating both immune and nonimmune cell metabolism.

Natural killer (NK) cell-based treatments have been reported as solid and effective therapies for some cancer entities. Activated NK cells undergo significant shifts in cellular metabolic pathways, with a shift towards glycolysis and mitochondrial oxidative phosphorylation (OXPHOS). Growing evidence suggests that the PI3K–AKT–mTOR pathway is crucial for modulating the development, differentiation, and activation of NK cells. PD-1 may exhibit its inhibitory function on NK cells by decreasing PI3K/AKT signaling in HCC. It was also previously reported that energy metabolism and cell motility deficiencies of NK cells are accountable as prominent mechanisms for NK-cell dysfunction in HCC patients. The metabolic changes in NK cells restrict their effector functions in cancer immune therapy.

Due to the metabolic reprogramming, the interaction between PI3K/AKT/mTOR and the metabolism can also alter the immune suppression network, which is widely present in different cancers. The PI3K/AKT/mTOR signaling pathway was shown to be activated in HCC tumor cells with a pronounced glycolytic metabolism leading to the accumulation of lactate.

A dedicated table on the role of metabolism-associated genes, proteins, and molecules from this review can be found in Table 1.

5. Targeting the PI3K/AKT/mTOR Pathway for HCC Therapy

The multi-kinase inhibitor regorafenib is used as a second-line agent after sorafenib failure in HCC patients and represents a valuable and relatively safe therapeutic option that brings new hope for HCC therapy. More than half of the HCC patients show constitutive activation of the PI3K/AKT/mTOR pathway. The metabolic dependencies of cancer cells may be further investigated for anti-tumor therapy. For example, various cancer entities are dependent on constitutive signaling through the PI3K/AKT signaling axis. Currently, inhibitors targeting the PI3K/AKT signaling axis and different downstream pathways are in clinical trials (Table 2).

Copanlisib, a PI3K inhibitor recently approved for clinical use, strongly inhibited cell viability and colony formation in HCC cell lines. The study met its primary end point with an objective response rate of 16%, with copanlisib showing promising clinical activity in selected tumors with the PIK3CA mutation. Capivasertib has been shown to restrict p53 to the nucleus and activate the autophagy of hepatocytes, indicating that AKT inhibitors may become a potential treatment for HCC patients. Ipatasertib is a highly selective oral small-molecule inhibitor of AKT. In the FAIRLINE randomized clinical trial, a correlation between phosphorylated AKT expression and clinical outcome has been demonstrated in triple-negative breast cancer. Interestingly, the results from this trial implicated that even in the absence of mutations within the PIK3CA, AKT1, or PTEN genes, patients benefitted from ipatasertib treatment.

Moreover, it has been demonstrated that the mTOR inhibitor everolimus can improve the survival of HCC patients after LT. CC-223, a selective and orally bioavailable mTOR kinase inhibitor, blocked mitochondrial function and conducted ROS production in HCC cell lines. In vitro models as well as murine models mouse model illustrated HCC cell susceptibility for treatment with the mTOR inhibitors rapamycin and sapanisertib. There are some clinical trials targeting this pathway on progress in HCC (Figure 6).

6. Present Challenges and Future Directions

Due to the fact that the PI3K/AKT/mTOR pathway is critically involved in several cellular processes, targeting the PI3K/AKT/mTOR pathway leads to adverse events that lead to early treatment or study cancellation. In addition, treatment resistance after PI3K/AKT/mTOR pathway inhibition has been observed. Therefore, new drugs or combination therapies need to be studied to make PI3K/AKT/mTOR inhibitors more tolerable and efficient. Combination therapies are becoming a crucial part of the development of new drug, and a better treatment for cancer. Dual targeting of AKT and mTOR may be a potential treatment option for HCC patients, as demonstrated in preclinical models. Furthermore, clinical trials combining mTOR inhibitors with both chemotherapy and radiotherapy are ongoing. Furthermore, new therapeutic strategies, e.g., radiosensitization, have been proposed for HCC patients. Recently, a new set of selective mTOR inhibitors was developed that increased the radiosensitivity of HCC cells. These results underline the potential applications of PI3K/AKT/mTOR inhibitors as additive treatments or as combination partners for other drugs. The combination of therapies may become the future HCC treatment direction.

7. Summary and Conclusions

In recent years, many studies have analyzed the role of the PI3K/AKT/mTOR signaling pathway in the development of HCC. The research on the PI3K/AKT/mTOR signaling pathway contributed to and resulted in the development of inhibitors for HCC treatment. However, the clinical benefits of single-agent therapy using these inhibitors are still limited. The interaction between PI3K/AKT/mTOR signaling and metabolism demonstrates the close connection between the oncogenic signaling network and tumor metabolism. Future research focusing on the crosstalk between the PI3K/AKT/mTOR signaling axis and the cellular metabolism in HCC may help to reveal the impact of metabolic reprogramming in cancer cells and contribute to the development of novel potential therapeutic agents.

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    Ellis H., Ma C.X. PI3K Inhibitors in Breast Cancer Therapy. Curr. Oncol. Rep. 2019;21:110.

    Not in our library10.1007/s11912-019-0846-7

  17. 17.

    Vanhaesebroeck B., Guillermet-Guibert J., Graupera M., Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat. Rev. Mol. Cell Biol. 2010;11:329-341.

    Not in our library10.1038/nrm2882

  18. 18.

    Thorpe L.M., Yuzugullu H., Zhao J.J. PI3K in cancer: Divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer. 2015;15:7-24.

    Not in our library10.1038/nrc3860

  19. 19.

    Liu W., Zheng L., Zhang R., Hou P., Wang J., Wu L., Li J. Circ-ZEB1 promotes PIK3CA expression by silencing miR-199a-3p and affects the proliferation and apoptosis of hepatocellular carcinoma. Mol. Cancer. 2022;21:72.

    Not in our library10.1186/s12943-022-01529-5

  20. 20.

    Xin Z., Li J., Zhang H., Zhou Y., Song J., Chen P., Bai L., Chen H., Zhou J., Chen J., et al. Cancer Genomic Alterations Can Be Potential Biomarkers Predicting Microvascular Invasion and Early Recurrence of Hepatocellular Carcinoma. Front Oncol. 2022;12:783109.

    Not in our library10.3389/fonc.2022.783109

  21. 21.

    Zeng C., Yuan G., Hu Y., Wang D., Shi X., Zhu D., Hu A., Meng Y., Lu J. Repressing phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma by microRNA-142-3p restrains the progression of hepatocellular carcinoma. Bioengineered. 2022;13:1491-1506.

    Not in our library10.1080/21655979.2021.2020549

  22. 22.

    Fang Y., Xue J.L., Shen Q., Chen J., Tian L. MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology. 2012;55:1852-1862.

    Not in our library10.1002/hep.25576

  23. 23.

    Gulluni F., De Santis M.C., Margaria J.P., Martini M., Hirsch E. Class II PI3K Functions in Cell Biology and Disease. Trends Cell Biol. 2019;29:339-359.

    Not in our library10.1016/j.tcb.2019.01.001

  24. 24.

    Chai Z.T., Kong J., Zhu X.D., Zhang Y.Y., Lu L., Zhou J.M., Wang L.R., Zhang K.Z., Zhang Q.B., Ao J.Y., et al. MicroRNA-26a inhibits angiogenesis by down-regulating VEGFA through the PIK3C2alpha/Akt/HIF-1alpha pathway in hepatocellular carcinoma. PLoS ONE. 2013;8:e77957.

    Not in our library10.1371/journal.pone.0077957

  25. 25.

    Maehama T., Fukasawa M., Date T., Wakita T., Hanada K. A class II phosphoinositide 3-kinase plays an indispensable role in hepatitis C virus replication. Biochem. Biophys Res. Commun. 2013;440:150-156.

    Not in our library10.1016/j.bbrc.2013.09.048

  26. 26.

    Ronan B., Flamand O., Vescovi L., Dureuil C., Durand L., Fassy F., Bachelot M.F., Lamberton A., Mathieu M., Bertrand T., et al. A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat. Chem. Biol. 2014;10:1013-1019.

    Not in our library10.1038/nchembio.1681

  27. 27.

    Liu F., Wu X., Qian Y., Jiang X., Wang Y., Gao J. PIK3C3 regulates the expansion of liver CSCs and PIK3C3 inhibition counteracts liver cancer stem cell activity induced by PI3K inhibitor. Cell Death Dis. 2020;11:427.

    Not in our library10.1038/s41419-020-2631-9

  28. 28.

    Vasudevan K.M., Barbie D.A., Davies M.A., Rabinovsky R., McNear C.J., Kim J.J., Hennessy B.T., Tseng H., Pochanard P., Kim S.Y., et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell. 2009;16:21-32.

    Not in our library10.1016/j.ccr.2009.04.012

  29. 29.

    Wang Q., Yu W.N., Chen X., Peng X.D., Jeon S.M., Birnbaum M.J., Guzman G., Hay N. Spontaneous Hepatocellular Carcinoma after the Combined Deletion of Akt Isoforms. Cancer Cell. 2016;29:523-535.

    Not in our library10.1016/j.ccell.2016.02.008

  30. 30.

    Xu Z., Xu M., Liu P., Zhang S., Shang R., Qiao Y., Che L., Ribback S., Cigliano A., Evert K., et al. The mTORC2-Akt1 Cascade Is Crucial for c-Myc to Promote Hepatocarcinogenesis in Mice and Humans. Hepatology. 2019;70:1600-1613.

    Not in our library10.1002/hep.30697

  31. 31.

    Xu X., Sakon M., Nagano H., Hiraoka N., Yamamoto H., Hayashi N., Dono K., Nakamori S., Umeshita K., Ito Y., et al. Akt2 expression correlates with prognosis of human hepatocellular carcinoma. Oncol. Rep. 2004;11:25-32.

    Not in our library10.3892/or.11.1.25

  32. 32.

    Galicia V.A., He L., Dang H., Kanel G., Vendryes C., French B.A., Zeng N., Bayan J.A., Ding W., Wang K.S., et al. Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. Gastroenterology. 2010;139:2170-2182.

    Not in our library10.1053/j.gastro.2010.09.002

  33. 33.

    Hsieh A.C., Liu Y., Edlind M.P., Ingolia N.T., Janes M.R., Sher A., Shi E.Y., Stumpf C.R., Christensen C., Bonham M.J., et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature. 2012;485:55-61.

    Not in our library10.1038/nature10912

  34. 34.

    Hara K., Maruki Y., Long X., Yoshino K., Oshiro N., Hidayat S., Tokunaga C., Avruch J., Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110:177-189.

    Not in our library10.1016/s0092-8674(02)00833-4

  35. 35.

    Dancey J. mTOR signaling and drug development in cancer. Nat. Rev. Clin. Oncol. 2010;7:209-219.

    Not in our library10.1038/nrclinonc.2010.21

  36. 36.

    Golob-Schwarzl N., Krassnig S., Toeglhofer A.M., Park Y.N., Gogg-Kamerer M., Vierlinger K., Schroder F., Rhee H., Schicho R., Fickert P., et al. New liver cancer biomarkers: PI3K/AKT/mTOR pathway members and eukaryotic translation initiation factors. Eur. J. Cancer. 2017;83:56-70.

    Not in our library10.1016/j.ejca.2017.06.003

  37. 37.

    Bhat M., Sonenberg N., Gores G.J. The mTOR pathway in hepatic malignancies. Hepatology. 2013;58:810-818.

    Not in our library10.1002/hep.26323

  38. 38.

    Umemura A., Park E.J., Taniguchi K., Lee J.H., Shalapour S., Valasek M.A., Aghajan M., Nakagawa H., Seki E., Hall M.N., et al. Liver damage, inflammation, and enhanced tumorigenesis after persistent mTORC1 inhibition. Cell Metab. 2014;20:133-144.

    Not in our library10.1016/j.cmet.2014.05.001

  39. 39.

    Guri Y., Colombi M., Dazert E., Hindupur S.K., Roszik J., Moes S., Jenoe P., Heim M.H., Riezman I., Riezman H., et al. mTORC2 Promotes Tumorigenesis via Lipid Synthesis. Cancer Cell. 2017;32:807-823 e812.

    Not in our library10.1016/j.ccell.2017.11.011

  40. 40.

    Zhong X.Y., Yuan X.M., Xu Y.Y., Yin M., Yan W.W., Zou S.W., Wei L.M., Lu H.J., Wang Y.P., Lei Q.Y. CARM1 Methylates GAPDH to Regulate Glucose Metabolism and Is Suppressed in Liver Cancer. Cell Rep. 2018;24:3207-3223.

    Not in our library10.1016/j.celrep.2018.08.066

  41. 41.
    Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice · 2016
    No notice
  42. 42.

    Liu Y., Zhao Y., Guo L. Effects of orexin A on glucose metabolism in human hepatocellular carcinoma in vitro via PI3K/Akt/mTOR-dependent and -independent mechanism. Mol. Cell Endocrinol. 2016;420:208-216.

    Not in our library10.1016/j.mce.2015.11.002

  43. 43.

    Zhang Y., Zhang C., Zhao Q., Wei W., Dong Z., Shao L., Li J., Wu W., Zhang H., Huang H., et al. The miR-873/NDFIP1 axis promotes hepatocellular carcinoma growth and metastasis through the AKT/mTOR-mediated Warburg effect. Am. J. Cancer Res. 2019;9:927-944.

    Not in our library

  44. 44.

    Ye G., Qin Y., Wang S., Pan D., Xu S., Wu C., Wang X., Wang J., Ye H., Shen H. Lamc1 promotes the Warburg effect in hepatocellular carcinoma cells by regulating PKM2 expression through AKT pathway. Cancer Biol. Ther. 2019;20:711-719.

    Not in our library10.1080/15384047.2018.1564558

  45. 45.

    Chen X.S., Li L.Y., Guan Y.D., Yang J.M., Cheng Y. Anticancer strategies based on the metabolic profile of tumor cells: Therapeutic targeting of the Warburg effect. Acta Pharmacol. Sin. 2016;37:1013-1019.

    Not in our library10.1038/aps.2016.47

  46. 46.

    Cui H., Gao Q., Zhang L., Han F., Wang L. Knockdown of FOXK1 suppresses liver cancer cell viability by inhibiting glycolysis. Life Sci. 2018;213:66-73.

    Not in our library10.1016/j.lfs.2018.10.018

  47. 47.

    Liu G., Shi A., Wang N., Li M., He X., Yin C., Tu Q., Shen X., Tao Y., Wang Q., et al. Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity. Redox Biol. 2020;37:101701.

    Not in our library10.1016/j.redox.2020.101701

  48. 48.

    Lu C., Yang D., Klement J.D., Colson Y.L., Oberlies N.H., Pearce C.J., Colby A.H., Grinstaff M.W., Liu Z., Shi H., et al. H3K9me3 represses G6PD expression to suppress the pentose phosphate pathway and ROS production to promote human mesothelioma growth. Oncogene. 2022;41:2651-2662.

    Not in our library10.1038/s41388-022-02283-0

  49. 49.
    O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth · 2015
    No notice
  50. 50.

    Lin R., Elf S., Shan C., Kang H.B., Ji Q., Zhou L., Hitosugi T., Zhang L., Zhang S., Seo J.H., et al. 6-Phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumour growth by inhibiting LKB1-AMPK signalling. Nat. Cell Biol. 2015;17:1484-1496.

    Not in our library10.1038/ncb3255

  51. 51.

    Mitsuishi Y., Taguchi K., Kawatani Y., Shibata T., Nukiwa T., Aburatani H., Yamamoto M., Motohashi H. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22:66-79.

    Not in our library10.1016/j.ccr.2012.05.016

  52. 52.

    Chen H., Wu D., Bao L., Yin T., Lei D., Yu J., Tong X. 6PGD inhibition sensitizes hepatocellular carcinoma to chemotherapy via AMPK activation and metabolic reprogramming. Biomed. Pharmacother. 2019;111:1353-1358.

    Not in our library10.1016/j.biopha.2019.01.028

  53. 53.
    TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism · 2020
    No notice
  54. 54.

    Zhangyuan G., Wang F., Zhang H., Jiang R., Tao X., Yu D., Jin K., Yu W., Liu Y., Yin Y., et al. VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR-PI3K-AKT pathway. Oncogene. 2020;39:1213-1230.

    Not in our library10.1038/s41388-019-1052-7

  55. 55.
    The fatty acid receptor CD36 promotes HCC progression through activating Src/PI3K/AKT axis-dependent aerobic glycolysis · 2021
    No notice
  56. 56.

    Lundo K., Trauelsen M., Pedersen S.F., Schwartz T.W. Why Warburg Works: Lactate Controls Immune Evasion through GPR81. Cell Metab. 2020;31:666-668.

    Not in our library10.1016/j.cmet.2020.03.001

  57. 57.

    Huang Q., Li J., Xing J., Li W., Li H., Ke X., Zhang J., Ren T., Shang Y., Yang H., et al. CD147 promotes reprogramming of glucose metabolism and cell proliferation in HCC cells by inhibiting the p53-dependent signaling pathway. J. Hepatol. 2014;61:859-866.

    Not in our library10.1016/j.jhep.2014.04.035

  58. 58.
    The Genomic Analysis of Lactic Acidosis and Acidosis Response in Human Cancers · 2008
    No notice
  59. 59.

    Alannan M., Fayyad-Kazan H., Trezeguet V., Merched A. Targeting Lipid Metabolism in Liver Cancer. Biochemistry. 2020;59:3951-3964.

    Not in our library10.1021/acs.biochem.0c00477

  60. 60.

    Kim Y.S., Lee Y.M., Oh T.I., Shin D.H., Kim G.H., Kan S.Y., Kang H., Kim J.H., Kim B.M., Yim W.J., et al. Emodin Sensitizes Hepatocellular Carcinoma Cells to the Anti-Cancer Effect of Sorafenib through Suppression of Cholesterol Metabolism. Int. J. Mol. Sci. 2018;19:3127.

    Not in our library10.3390/ijms19103127

  61. 61.

    Zhu Q.W., Yu Y., Zhang Y., Wang X.H. VLCAD inhibits the proliferation and invasion of hepatocellular cancer cells through regulating PI3K/AKT axis. Clin. Transl. Oncol. 2022;24:864-874.

    Not in our library10.1007/s12094-021-02733-3

  62. 62.

    Cheng Y.H., Ko Y.C., Ku H.J., Huang C.C., Yao Y.C., Liao Y.T., Chen Y.T., Huang S.F., Huang L.R. Novel Paired Cell Lines for the Study of Lipid Metabolism and Cancer Stemness of Hepatocellular Carcinoma. Front Cell Dev. Biol. 2022;10:821224.

    Not in our library10.3389/fcell.2022.821224

  63. 63.

    Li J., Huang Q., Long X., Zhang J., Huang X., Aa J., Yang H., Chen Z., Xing J. CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARalpha pathways. J. Hepatol. 2015;63:1378-1389.

    Not in our library10.1016/j.jhep.2015.07.039

  64. 64.

    Hu J., Hong W., Yao K.N., Zhu X.H., Chen Z.Y., Ye L. Ursodeoxycholic acid ameliorates hepatic lipid metabolism in LO2 cells by regulating the AKT/mTOR/SREBP-1 signaling pathway. World J. Gastroenterol. 2019;25:1492-1501.

    Not in our library10.3748/wjg.v25.i12.1492

  65. 65.

    Bort A., Sanchez B.G., Mateos-Gomez P.A., Diaz-Laviada I., Rodriguez-Henche N. Capsaicin Targets Lipogenesis in HepG2 Cells Through AMPK Activation, AKT Inhibition and PPARs Regulation. Int. J. Mol. Sci. 2019;20:1660.

    Not in our library10.3390/ijms20071660

  66. 66.

    Shimano H., Sato R. SREBP-regulated lipid metabolism: Convergent physiology—Divergent pathophysiology. Nat. Rev. Endocrinol. 2017;13:710-730.

    Not in our library10.1038/nrendo.2017.91

  67. 67.

    Calvisi D.F., Wang C., Ho C., Ladu S., Lee S.A., Mattu S., Destefanis G., Delogu S., Zimmermann A., Ericsson J., et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140:1071-1083.

    Not in our library10.1053/j.gastro.2010.12.006

  68. 68.

    Yin F., Sharen G., Yuan F., Peng Y., Chen R., Zhou X., Wei H., Li B., Jing W., Zhao J. TIP30 regulates lipid metabolism in hepatocellular carcinoma by regulating SREBP1 through the Akt/mTOR signaling pathway. Oncogenesis. 2017;6:e347.

    Not in our library10.1038/oncsis.2017.49

  69. 69.

    Li L., Pilo G.M., Li X., Cigliano A., Latte G., Che L., Joseph C., Mela M., Wang C., Jiang L., et al. Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans. J. Hepatol. 2016;64:333-341.

    Not in our library10.1016/j.jhep.2015.10.004

  70. 70.

    Li L., Che L., Tharp K.M., Park H.M., Pilo M.G., Cao D., Cigliano A., Latte G., Xu Z., Ribback S., et al. Differential requirement for de novo lipogenesis in cholangiocarcinoma and hepatocellular carcinoma of mice and humans. Hepatology. 2016;63:1900-1913.

    Not in our library10.1002/hep.28508

  71. 71.

    Qiu Z., Zhang C., Zhou J., Hu J., Sheng L., Li X., Chen L., Li X., Deng X., Zheng G. Celecoxib alleviates AKT/c-Met-triggered rapid hepatocarcinogenesis by suppressing a novel COX-2/AKT/FASN cascade. Mol. Carcinog. 2019;58:31-41.

    Not in our library10.1002/mc.22904

  72. 72.

    Chen J., Chen J., Huang J., Li Z., Gong Y., Zou B., Liu X., Ding L., Li P., Zhu Z., et al. HIF-2alpha upregulation mediated by hypoxia promotes NAFLD-HCC progression by activating lipid synthesis via the PI3K-AKT-mTOR pathway. Aging. 2019;11:10839-10860.

    Not in our library10.18632/aging.102488

  73. 73.

    He F., Antonucci L., Yamachika S., Zhang Z., Taniguchi K., Umemura A., Hatzivassiliou G., Roose-Girma M., Reina-Campos M., Duran A., et al. NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly. J. Hepatol. 2020;72:1182-1195.

    Not in our library10.1016/j.jhep.2020.01.023

  74. 74.

    Altman B.J., Stine Z.E., Dang C.V. From Krebs to clinic: Glutamine metabolism to cancer therapy. Nat. Rev. Cancer. 2016;16:619-634.

    Not in our library10.1038/nrc.2016.71

  75. 75.

    Ananieva E. Targeting amino acid metabolism in cancer growth and anti-tumor immune response. World J. Biol. Chem. 2015;6:281-289.

    Not in our library10.4331/wjbc.v6.i4.281

  76. 76.

    Tennant D.A., Duran R.V., Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat. Rev. Cancer. 2010;10:267-277.

    Not in our library10.1038/nrc2817

  77. 77.

    Jewell J.L., Kim Y.C., Russell R.C., Yu F.X., Park H.W., Plouffe S.W., Tagliabracci V.S., Guan K.L. Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science. 2015;347:194-198.

    Not in our library10.1126/science.1259472

  78. 78.
    A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer · 2020
    No notice
  79. 79.

    Xi J., Sun Y., Zhang M., Fa Z., Wan Y., Min Z., Xu H., Xu C., Tang J. GLS1 promotes proliferation in hepatocellular carcinoma cells via AKT/GSK3beta/CyclinD1 pathway. Exp. Cell Res. 2019;381:1-9.

    Not in our library10.1016/j.yexcr.2019.04.005

  80. 80.

    Wei Y., Tang X., Ren Y., Yang Y., Song F., Fu J., Liu S., Yu M., Chen J., Wang S., et al. An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity. Signal. Transduct. Target Ther. 2021;6:421.

    Not in our library10.1038/s41392-021-00801-2

  81. 81.

    Ding M., Bu X., Li Z., Xu H., Feng L., Hu J., Wei X., Gao J., Tao Y., Cai B., et al. NDRG2 ablation reprograms metastatic cancer cells towards glutamine dependence via the induction of ASCT2. Int. J. Biol. Sci. 2020;16:3100-3115.

    Not in our library10.7150/ijbs.48066

  82. 82.

    Feun L., You M., Wu C.J., Kuo M.T., Wangpaichitr M., Spector S., Savaraj N. Arginine deprivation as a targeted therapy for cancer. Curr. Pharm. Des. 2008;14:1049-1057.

    Not in our library10.2174/138161208784246199

  83. 83.

    Saha A., Connelly S., Jiang J., Zhuang S., Amador D.T., Phan T., Pilz R.B., Boss G.R. Akt phosphorylation and regulation of transketolase is a nodal point for amino acid control of purine synthesis. Mol. Cell. 2014;55:264-276.

    Not in our library10.1016/j.molcel.2014.05.028

  84. 84.

    Lee C., Raffaghello L., Brandhorst S., Safdie F.M., Bianchi G., Martin-Montalvo A., Pistoia V., Wei M., Hwang S., Merlino A., et al. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 2012;4:124-127.

    Not in our library10.1126/scitranslmed.3003293

  85. 85.

    Cox A.G., Hwang K.L., Brown K.K., Evason K., Beltz S., Tsomides A., O’Connor K., Galli G.G., Yimlamai D., Chhangawala S., et al. Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growth. Nat. Cell Biol. 2016;18:886-896.

    Not in our library10.1038/ncb3389

  86. 86.

    Dimri M., Humphries A., Laknaur A., Elattar S., Lee T.J., Sharma A., Kolhe R., Satyanarayana A. NAD(P)H Quinone Dehydrogenase 1 Ablation Inhibits Activation of the Phosphoinositide 3-Kinase/Akt Serine/Threonine Kinase and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Pathways and Blocks Metabolic Adaptation in Hepatocellular Carcinoma. Hepatology. 2020;71:549-568.

    Not in our library10.1002/hep.30818

  87. 87.

    Bidkhori G., Benfeitas R., Klevstig M., Zhang C., Nielsen J., Uhlen M., Boren J., Mardinoglu A. Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes. Proc. Natl. Acad. Sci. USA. 2018;115:E11874-E11883.

    Not in our library10.1073/pnas.1807305115

  88. 88.

    Ben-Sahra I., Howell J.J., Asara J.M., Manning B.D. Stimulation of de novo pyrimidine synthesis by growth signaling through mTOR and S6K1. Science. 2013;339:1323-1328.

    Not in our library10.1126/science.1228792

  89. 89.
    A non-proliferative role of pyrimidine metabolism in cancer · 2020
    Not checked
  90. 90.

    Wang X., Yang K., Wu Q., Kim L.J.Y., Morton A.R., Gimple R.C., Prager B.C., Shi Y., Zhou W., Bhargava S., et al. Targeting pyrimidine synthesis accentuates molecular therapy response in glioblastoma stem cells. Sci. Transl. Med. 2019;11:4972.

    Not in our library10.1126/scitranslmed.aau4972

  91. 91.

    Ridder D.A., Schindeldecker M., Weinmann A., Berndt K., Urbansky L., Witzel H.R., Heinrich S., Roth W., Straub B.K. Key Enzymes in Pyrimidine Synthesis, CAD and CPS1, Predict Prognosis in Hepatocellular Carcinoma. Cancers. 2021;13:744.

    Not in our library10.3390/cancers13040744

  92. 92.

    Zhu Z., Cao C., Zhang D., Zhang Z., Liu L., Wu D., Sun J. UBE2T-mediated Akt ubiquitination and Akt/beta-catenin activation promotes hepatocellular carcinoma development by increasing pyrimidine metabolism. Cell Death Dis. 2022;13:154.

    Not in our library10.1038/s41419-022-04596-0

  93. 93.

    Chong Y.C., Toh T.B., Chan Z., Lin Q.X.X., Thng D.K.H., Hooi L., Ding Z., Shuen T., Toh H.C., Dan Y.Y., et al. Targeted Inhibition of Purine Metabolism Is Effective in Suppressing Hepatocellular Carcinoma Progression. Hepatol. Commun. 2020;4:1362-1381.

    Not in our library10.1002/hep4.1559

  94. 94.

    Fu Y., Liu S., Rodrigues R.M., Han Y., Guo C., Zhu Z., He Y., Mackowiak B., Feng D., Gao B., et al. Activation of VIPR1 suppresses hepatocellular carcinoma progression by regulating arginine and pyrimidine metabolism. Int. J. Biol. Sci. 2022;18:4341-4356.

    Not in our library10.7150/ijbs.71134

  95. 95.
    Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine · 2021
    No notice
  96. 96.
    Arsenene-mediated multiple independently targeted reactive oxygen species burst for cancer therapy · 2021
    No notice
  97. 97.

    Lim S.O., Gu J.M., Kim M.S., Kim H.S., Park Y.N., Park C.K., Cho J.W., Park Y.M., Jung G. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: Methylation of the E-cadherin promoter. Gastroenterology. 2008;135:2128-2140.

    Not in our library10.1053/j.gastro.2008.07.027

  98. 98.

    Nogueira V., Park Y., Chen C.C., Xu P.Z., Chen M.L., Tonic I., Unterman T., Hay N. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell. 2008;14:458-470.

    Not in our library10.1016/j.ccr.2008.11.003

  99. 99.

    Silva A., Girio A., Cebola I., Santos C.I., Antunes F., Barata J.T. Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells. Leukemia. 2011;25:960-967.

    Not in our library10.1038/leu.2011.56

  100. 100.

    Zhao Z., Gao J., Li C., Xu X., Hu Y., Huang S. Reactive Oxygen Species Induce Endothelial Differentiation of Liver Cancer Stem-Like Sphere Cells through the Activation of Akt/IKK Signaling Pathway. Oxid. Med. Cell Longev. 2020;2020:1621687.

    Not in our library10.1155/2020/1621687

  101. 101.

    Orci L.A., Lacotte S., Delaune V., Slits F., Oldani G., Lazarevic V., Rossetti C., Rubbia-Brandt L., Morel P., Toso C. Effects of the gut-liver axis on ischaemia-mediated hepatocellular carcinoma recurrence in the mouse liver. J. Hepatol. 2018;68:978-985.

    Not in our library10.1016/j.jhep.2017.12.025

  102. 102.

    Ng K.T., Yeung O.W., Lam Y.F., Liu J., Liu H., Pang L., Yang X.X., Zhu J., Zhang W., Lau M.Y.H., et al. Glutathione S-transferase A2 promotes hepatocellular carcinoma recurrence after liver transplantation through modulating reactive oxygen species metabolism. Cell Death Discov. 2021;7:188.

    Not in our library10.1038/s41420-021-00569-y

  103. 103.

    Wan J., Liu T., Mei L., Li J., Gong K., Yu C., Li W. Synergistic antitumour activity of sorafenib in combination with tetrandrine is mediated by reactive oxygen species (ROS)/Akt signaling. Br. J. Cancer. 2013;109:342-350.

    Not in our library10.1038/bjc.2013.334

  104. 104.
    β-Thujaplicin induces autophagic cell death, apoptosis, and cell cycle arrest through ROS-mediated Akt and p38/ERK MAPK signaling in human hepatocellular carcinoma · 2019
    No notice
  105. 105.

    Liu C., Gong K., Mao X., Li W. Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma. Int. J. Cancer. 2011;129:1519-1531.

    Not in our library10.1002/ijc.25817

  106. 106.

    Farazi P.A., DePinho R.A. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat. Rev. Cancer. 2006;6:674-687.

    Not in our library10.1038/nrc1934

  107. 107.
    HBx increases chromatin accessibility and ETV4 expression to regulate dishevelled-2 and promote HCC progression · 2022
    Not checked
  108. 108.

    Ha H.L., Yu D.Y. HBx-induced reactive oxygen species activates hepatocellular carcinogenesis via dysregulation of PTEN/Akt pathway. World J. Gastroenterol. 2010;16:4932-4937.

    Not in our library10.3748/wjg.v16.i39.4932

  109. 109.

    Ko E., Seo H.W., Jung G. Telomere length and reactive oxygen species levels are positively associated with a high risk of mortality and recurrence in hepatocellular carcinoma. Hepatology. 2018;67:1378-1391.

    Not in our library10.1002/hep.29604

  110. 110.

    Ren T., Wang J., Zhang H., Yuan P., Zhu J., Wu Y., Huang Q., Guo X., Zhang J., Ji L., et al. MCUR1-Mediated Mitochondrial Calcium Signaling Facilitates Cell Survival of Hepatocellular Carcinoma via Reactive Oxygen Species-Dependent P53 Degradation. Antioxid. Redox. Signal. 2018;28:1120-1136.

    Not in our library10.1089/ars.2017.6990

  111. 111.

    Wu J.R., You R.I., Hu C.T., Cheng C.C., Rudy R., Wu W.S. Hydrogen peroxide inducible clone-5 sustains NADPH oxidase-dependent reactive oxygen species-c-jun N-terminal kinase signaling in hepatocellular carcinoma. Oncogenesis. 2019;8:40.

    Not in our library10.1038/s41389-019-0149-8

  112. 112.
    Exosome-mediated communication in the tumor microenvironment contributes to hepatocellular carcinoma development and progression · 2019
    No notice
  113. 113.
    PD1Hi CD8+ T cells correlate with exhausted signature and poor clinical outcome in hepatocellular carcinoma · 2019
    No notice
  114. 114.

    Martinez-Reyes I., Chandel N.S. Cancer metabolism: Looking forward. Nat. Rev. Cancer. 2021;21:669-680.

    Not in our library10.1038/s41568-021-00378-6

  115. 115.

    Chang C.H., Qiu J., O’Sullivan D., Buck M.D., Noguchi T., Curtis J.D., Chen Q., Gindin M., Gubin M.M., van der Windt G.J., et al. Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015;162:1229-1241.

    Not in our library10.1016/j.cell.2015.08.016

  116. 116.

    Vitale I., Manic G., Coussens L.M., Kroemer G., Galluzzi L. Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 2019;30:36-50.

    Not in our library10.1016/j.cmet.2019.06.001

  117. 117.

    Colegio O.R., Chu N.Q., Szabo A.L., Chu T., Rhebergen A.M., Jairam V., Cyrus N., Brokowski C.E., Eisenbarth S.C., Phillips G.M., et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559-563.

    Not in our library10.1038/nature13490

  118. 118.

    Vergadi E., Ieronymaki E., Lyroni K., Vaporidi K., Tsatsanis C. Akt Signaling Pathway in Macrophage Activation and M1/M2 Polarization. J. Immunol. 2017;198:1006-1014.

    Not in our library10.4049/jimmunol.1601515

  119. 119.

    Zhou H.C., Xin-Yan Y., Yu W.W., Liang X.Q., Du X.Y., Liu Z.C., Long J.P., Zhao G.H., Liu H.B. Lactic acid in macrophage polarization: The significant role in inflammation and cancer. Int. Rev. Immunol. 2022;41:4-18.

    Not in our library10.1080/08830185.2021.1955876

  120. 120.

    Zhang Q., Lou Y., Bai X.L., Liang T.B. Immunometabolism: A novel perspective of liver cancer microenvironment and its influence on tumor progression. World J. Gastroenterol. 2018;24:3500-3512.

    Not in our library10.3748/wjg.v24.i31.3500

  121. 121.

    Finlay D., Cantrell D.A. Metabolism, migration and memory in cytotoxic T cells. Nat. Rev. Immunol. 2011;11:109-117.

    Not in our library10.1038/nri2888

  122. 122.
    Protein Kinase B Controls Transcriptional Programs that Direct Cytotoxic T Cell Fate but Is Dispensable for T Cell Metabolism · 2011
    No notice
  123. 123.

    Crompton J.G., Sukumar M., Roychoudhuri R., Clever D., Gros A., Eil R.L., Tran E., Hanada K., Yu Z., Palmer D.C., et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 2015;75:296-305.

    Not in our library10.1158/0008-5472.can-14-2277

  124. 124.

    Basu S., Hubbard B., Shevach E.M. Foxp3-mediated inhibition of Akt inhibits Glut1 (glucose transporter 1) expression in human T regulatory cells. J. Leukoc. Biol. 2015;97:279-283.

    Not in our library10.1189/jlb.2ab0514-273rr

  125. 125.

    Yang P., Li Q.J., Feng Y., Zhang Y., Markowitz G.J., Ning S., Deng Y., Zhao J., Jiang S., Yuan Y., et al. TGF-beta-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 2012;22:291-303.

    Not in our library10.1016/j.ccr.2012.07.023

  126. 126.

    Francisco L.M., Salinas V.H., Brown K.E., Vanguri V.K., Freeman G.J., Kuchroo V.K., Sharpe A.H. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 2009;206:3015-3029.

    Not in our library10.1084/jem.20090847

  127. 127.

    Xia Y., Brown Z.J., Huang H., Tsung A. Metabolic reprogramming of immune cells: Shaping the tumor microenvironment in hepatocellular carcinoma. Cancer Med. 2021;10:6374-6383.

    Not in our library10.1002/cam4.4177

  128. 128.
    Impact of intracellular innate immune receptors on immunometabolism · 2021
    No notice
  129. 129.

    Myers J.A., Miller J.S. Exploring the NK cell platform for cancer immunotherapy. Nat. Rev. Clin. Oncol. 2021;18:85-100.

    Not in our library10.1038/s41571-020-0426-7

  130. 130.
    Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice · 2018
    No notice
  131. 131.
    IL-15–PI3K–AKT–mTOR: A Critical Pathway in the Life Journey of Natural Killer Cells · 2015
    No notice
  132. 132.

    Liu Y., Cheng Y., Xu Y., Wang Z., Du X., Li C., Peng J., Gao L., Liang X., Ma C. Increased expression of programmed cell death protein 1 on NK cells inhibits NK-cell-mediated anti-tumor function and indicates poor prognosis in digestive cancers. Oncogene. 2017;36:6143-6153.

    Not in our library10.1038/onc.2017.209

  133. 133.

    Zecca A., Barili V., Canetti D., Regina V., Olivani A., Carone C., Capizzuto V., Zerbato B., Trenti T., Dalla Valle R., et al. Energy metabolism and cell motility defect in NK-cells from patients with hepatocellular carcinoma. Cancer Immunol. Immunother. 2020;69:1589-1603.

    Not in our library10.1007/s00262-020-02561-4

  134. 134.
    NK Cell Metabolism and Tumor Microenvironment · 2019
    No notice
  135. 135.

    Speiser D.E., Ho P.C., Verdeil G. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 2016;16:599-611.

    Not in our library10.1038/nri.2016.80

  136. 136.

    Facciorusso A., Abd El Aziz M.A., Sacco R. Efficacy of Regorafenib in Hepatocellular Carcinoma Patients: A Systematic Review and Meta-Analysis. Cancers. 2019;12:36.

    Not in our library10.3390/cancers12010036

  137. 137.

    Villanueva A., Chiang D.Y., Newell P., Peix J., Thung S., Alsinet C., Tovar V., Roayaie S., Minguez B., Sole M., et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135:1972-1983.

    Not in our library10.1053/j.gastro.2008.08.008

  138. 138.

    Vander Heiden M.G., Cantley L.C., Thompson C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 2009;324:1029-1033.

    Not in our library10.1126/science.1160809

  139. 139.

    Ye L., Mayerle J., Ziesch A., Reiter F.P., Gerbes A.L., De Toni E.N. The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma. Cell Death Discov. 2019;5:86.

    Not in our library10.1038/s41420-019-0165-7

  140. 140.

    Damodaran S., Zhao F., Deming D.A., Mitchell E.P., Wright J.J., Gray R.J., Wang V., McShane L.M., Rubinstein L.V., Patton D.R., et al. Phase II Study of Copanlisib in Patients With Tumors With PIK3CA Mutations: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1F. J. Clin. Oncol. 2022;40:1552-1561.

    Not in our library10.1200/jco.21.01648

  141. 141.

    Patra T., Meyer K., Ray R.B., Ray R. A combination of AZD5363 and FH5363 induces lethal autophagy in transformed hepatocytes. Cell Death Dis. 2020;11:540.

    Not in our library10.1038/s41419-020-02741-1

  142. 142.

    Shi Z., Wulfkuhle J., Nowicka M., Gallagher R.I., Saura C., Nuciforo P.G., Calvo I., Andersen J., Passos-Coelho J.L., Gil-Gil M.J., et al. Functional Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer. Clin. Cancer Res. 2022;28:993-1003.

    Not in our library10.1158/1078-0432.ccr-21-2498

  143. 143.

    Yan X., Huang S., Yang Y., Lu Z., Li F., Jiang L., Jiang Y., Liu J. Sirolimus or Everolimus Improves Survival After Liver Transplantation for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. Liver Transpl. 2022;28:1063-1077.

    Not in our library10.1002/lt.26387

  144. 144.

    Xie Z., Wang J., Liu M., Chen D., Qiu C., Sun K. CC-223 blocks mTORC1/C2 activation and inhibits human hepatocellular carcinoma cells in vitro and in vivo. PLoS ONE. 2017;12:e0173252.

    Not in our library10.1371/journal.pone.0173252

  145. 145.

    Luo Y.D., Fang L., Yu H.Q., Zhang J., Lin X.T., Liu X.Y., Wu D., Li G.X., Huang D., Zhang Y.J., et al. p53 haploinsufficiency and increased mTOR signalling define a subset of aggressive hepatocellular carcinoma. J. Hepatol. 2021;74:96-108.

    Not in our library10.1016/j.jhep.2020.07.036

  146. 146.
    PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway? · 2022
    No notice
  147. 147.

    Rationalizing combination therapies. Nat. Med. 2017;23:1113.

    Not in our library10.1038/nm.4426

  148. 148.
    Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells · 2012
    Not checked
  149. 149.

    Asghar U., Meyer T. Are there opportunities for chemotherapy in the treatment of hepatocellular cancer? J. Hepatol. 2012;56:686-695.

    Not in our library10.1016/j.jhep.2011.07.031

  150. 150.

    Feng Y.Q., Gu S.X., Chen Y.S., Gao X.D., Ren Y.X., Chen J.C., Lu Y.Y., Zhang H., Cao S. Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma. Drug Des. Devel. Ther. 2020;14:1779-1798.

    Not in our library10.2147/dddt.s249156

  151. 151.

    Ferrin G., Guerrero M., Amado V., Rodriguez-Peralvarez M., De la Mata M. Activation of mTOR Signaling Pathway in Hepatocellular Carcinoma. Int. J. Mol. Sci. 2020;21:1266.

    Not in our library10.3390/ijms21041266

  152. 152.
    The Role of mTOR Signaling as a Therapeutic Target in Cancer · 2021
    No notice

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