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Decoding Signalling Pathways in Hepatocellular Carcinoma: Emerging Targets and Therapeutic Strategies (Part.I)

13 October 2025

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Figure 1. Etiology and Progression of Hepatocellular Carcinoma [1].

Hepatocellular carcinoma (HCC), the predominant form of liver cancer, remains one of the most challenging malignancies, ranking sixth in global incidence and third in cancer-related mortality [1].

Etiology and Disease Progression

The primary etiological factors for HCC include chronic HBV/HCV infections and metabolic disorders, such as non-alcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD), with aflatoxin exposure and hereditary liver conditions serving as significant contributors. These factors collectively promote hepatocarcinogenesis through mechanisms involving hepatic injury, inflammation, DNA mutations, and immune dysregulation.

Currently, HBV infection constitutes the principal cause of HCC, accounting for approximately 50% of cases globally; however, its incidence is gradually declining due to widespread vaccination and antiviral therapy implementation. Concurrently, NASH is emerging as an increasingly prevalent etiology for HCC [2].

Signalling Pathways

Dysregulation of multiple signalling pathways in HCC leads to uncontrolled cellular proliferation, metastasis, and recurrence. Understanding these critical pathways and their inhibitors is therefore essential for advancing HCC therapeutics. Cellular signalling pathways in HCC are typically categorized into two major groups: receptor tyrosine kinase (RTK) pathways and non-RTK pathways.

· RTK pathways

RTK pathways constitute the central drivers of HCC proliferation, angiogenesis, and therapeutic resistance. Among these, VEGFR, FGFR4, c-Met, and EGFR represent clinically validated therapeutic targets. Multi-targeted tyrosine kinase inhibitors (TKIs) such as Sorafenib and Lenvatinib, as well as immuno-angiogenesis combination regimens (e.g., Atezolizumab plus Bevacizumab), have become standard-of-care treatments for HCC. Nevertheless, resistance mechanisms and toxicity profiles remain significant clinical challenges.

Figure 2. RTK signalling pathways and their inhibitors in HCC [3].

· Vascular Endothelial Growth Factor Receptor (VEGFR)

1. Function: In hepatocellular carcinoma (HCC), VEGFR functions as a pivotal receptor tyrosine kinase (RTK) regulating tumor angiogenesis. Its ligand VEGF (particularly VEGFA) exhibits frequent amplification (7%-14%) and activates VEGFR1/2 to promote neovascularization, sustaining tumor nutrient supply and metastatic potential. Additionally, this pathway induces an immunosuppressive microenvironment through mechanisms such as myeloid-derived suppressor cell (MDSC) recruitment. VEGF serves as a metastatic biomarker in HCC patients [4].

2. Aberrant Expression: HCC demonstrates elevated VEGFR1/2 expression, which correlates with poor tumor differentiation, advanced staging, and unfavorable prognosis.

· Epidermal Growth Factor Receptor (EGFR)

1. Function: EGFR exhibits overexpression in more than 60% of HCC cases. EGFR activation promotes the induction of downstream signalling pathways including PI3K-AKT and MAPK, thereby enhancing tumor cell proliferation and survival. This overexpression correlates with poor differentiation, intrahepatic metastasis, and adverse clinical outcomes.

2. Aberrant Expression: While activating mutations in EGFR exons 18-21 are uncommon in HCC patients, research has identified 13 novel missense mutations in EGFR exons 19-23 within HCC tissue. Among these, seven variants (K757E, N808S, R831C, V897A, P937L, T940A, and M947T) confer resistance to first-generation EGFR inhibitors (Gefitinib, Lenvatinib), suggesting potential therapeutic utility for next-generation inhibitors such as Osimertinib [5].

· Hepatocyte Growth Factor Receptor (c-Met)

1. Function: The ligand for c-Met is hepatocyte growth factor (HGF). Their interaction activates MAPK and PI3K-AKT pathways, promoting cellular proliferation, epithelial-mesenchymal transition (EMT), and metastasis. c-Met functions as a critical driver of therapeutic resistance in HCC by circumventing Sorafenib/Lenvatinib target inhibition and maintaining downstream signalling.

2. Aberrant Expression: While c-Met mutations or amplifications occur in merely 1% of HCC cases, c-Met overexpression is observed in 25% of patients, increasing to 80% in advanced disease. This overexpression correlates with tumor invasiveness, recurrence, and therapeutic resistance [6].

· Fibroblast Growth Factor Receptor (FGFR)

1. Function: Within the FGFR family (FGFR1-4), the FGF19-FGFR4 axis represents a core driver in HCC pathogenesis. Through MAPK pathway activation, it promotes tumor proliferation, therapeutic resistance (to agents such as Sorafenib and Lenvatinib), and EMT. FGF19 frequently undergoes co-amplification with cyclin D1 in HCC, driving tumor progression [7].

2. Aberrant Expression: Dysregulation of FGF/FGFR signalling is present in 50% of HCC cases. FGFR4 demonstrates liver-specific elevated expression that progressively increases through the hepatic injury-cirrhosis-HCC continuum. This pattern establishes FGFR4 as a promising therapeutic target, with FGFR4 inhibitors such as Roblitinib and Fisogatinib demonstrating encouraging anticancer activity in HCC [8-9].

· Insulin-like Growth Factor Receptor (IGFR)

1. Function: IGFR1 binds IGF-1/2 to activate the PI3K-AKT pathway, regulating cellular survival and metabolism. Its overexpression correlates with advanced HCC and poor prognosis. While IGF-2R competitively binds IGF-2 to inhibit IGF-1R signalling, functioning as a putative tumor suppressor, it frequently undergoes loss of heterozygosity (LOH) and reduced expression in HCC, contrary to IGF-1R overexpression, thus failing to suppress IGFR1 signalling.

2. Aberrant Expression: IGF-1R overexpression and IGF-2 hypersecretion are common in HCC and exhibit cross-activation with insulin pathways, promoting therapeutic resistance [10-11].

· Platelet-Derived Growth Factor Receptor (PDGFR)

1. Function: PDGFR-α/β, upon PDGF ligand binding, activates MAPK/PI3K pathways to promote tumor stroma formation and angiogenesis [12].

2. Aberrant Expression: More than 50% of HCC cases demonstrate PDGFR-α overexpression, associated with increased microvascular density and elevated metastatic potential.

· c-Kit (Stem Cell Factor Receptor)

1. Function: c-Kit activation by stem cell factor (SCF) regulates cell survival and stemness properties. In HCC, it serves as a marker for liver cancer stem cells (LCSCs), with overexpression or mutations promoting LCSC self-renewal and therapeutic resistance. HBV/HCV infections can accelerate HCC development through c-Kit expression induction [13].

Figure 3. Targeting other key signalling pathways in HCC cells [3].

· TGF-β

1. Function: The TGF-β pathway operates through ligand binding (TGF-β1/2/3) to membrane receptors (TGF-βRI/II), activating downstream SMAD proteins (SMAD2/3/4) that form complexes translocating to the nucleus to regulate target gene expression. This pathway participates in cellular proliferation, differentiation, fibrosis, and immunomodulation [14].

2. Aberrant Expression (Dual Role): In early-stage tumors, TGF-β exerts tumor-suppressive effects by inhibiting cellular proliferation and inducing apoptosis. However, in advanced disease, sustained pathway activation promotes carcinogenesis through epithelial-mesenchymal transition (EMT) induction, angiogenesis enhancement, and immunosuppressive microenvironment remodeling (e.g., regulatory T-cell and M2 macrophage recruitment) [15].

3. Aberrant Expression (Mutations and Expression Abnormalities): Approximately 40% of HCC patients harbor somatic mutations in TGF-β pathway components (e.g., SMAD4, TGF-βRII). TGF-β1 frequently demonstrates overexpression in HCC, closely associated with hepatic fibrosis, tumor invasion/metastasis, and therapeutic resistance [16].

· Wnt

1. Function: Under normal conditions, β-catenin undergoes phosphorylation by the "destruction complex" (comprising APC, Axin, GSK3β, and other components) followed by degradation, maintaining pathway silence. When Wnt ligands bind to Frizzled receptors, the destruction complex disassembles, allowing β-catenin nuclear translocation and interaction with TCF/LEF transcription factors to activate target genes (e.g., c-Myc, Cyclin D1) that regulate cellular proliferation and stemness [17].

2. Aberrant Expression: Wnt/β-catenin pathway aberrations occur in 20%-35% of HCC cases, primarily arising from activating mutations in CTNNB1 (the gene encoding β-catenin) or inactivating mutations in AXIN1/APC. These alterations are particularly prevalent in HCV-associated, alcoholic, or non-viral HCC [18].

· Hedgehog

1. Function: The Hedgehog signalling pathway regulates cellular proliferation, differentiation, and tissue homeostasis through ligands (Shh, Ihh, Dhh), receptors (Ptch1, Smo), and Gli transcription factors. In the absence of ligands, Gli undergoes degradation to form repressor forms (GliR); upon ligand-receptor binding, Smo activation prevents Gli degradation, facilitating target gene transcription that drives cellular proliferation and differentiation.

2. Aberrant Expression: Hedgehog pathway activation is common in HCC, characterized by elevated expression of Shh, Ptch1, Smo, and Gli1. This activation correlates with hepatic fibrosis, hepatocarcinogenesis, cellular migration, and invasion, and contributes to resistance against therapeutics such as Sorafenib [19].

· Hippo and YAP

1. Function: The Hippo pathway phosphorylates YAP/TAZ through a kinase cascade (MST1/2→LATS1/2→YAP/TAZ), causing cytoplasmic retention and degradation. Upon pathway inactivation, YAP/TAZ translocate to the nucleus and associate with TEAD transcription factors, activating target genes (e.g., CTGF, CYR61) that regulate cellular proliferation and organ size.

2. Aberrant Expression (High-Frequency Activation): YAP/TAZ aberrant activation occurs in 65%-85% of HCC cases, primarily arising from Hippo pathway component (e.g., NF2, LATS1) inactivation or YAP gene amplification (5%-10%). YAP activation strongly correlates with high tumor invasiveness and unfavorable prognosis.

3. Aberrant Expression (Cross-Regulation): YAP/TAZ exhibits cross-activation with Wnt/β-catenin and EGFR pathways, promoting cancer stem cell properties and therapeutic resistance (e.g., to Lenvatinib) [20].

· Notch

1. Function: The Notch pathway operates through ligand-receptor interactions (Jagged/Delta with Notch1-4) between adjacent cells, triggering receptor cleavage that releases the Notch intracellular domain (NICD). This domain translocates to the nucleus and interacts with RBP-Jκ to regulate cellular differentiation, stem cell maintenance, and immunomodulation.

2. Aberrant Expression (Dual Role): In normal hepatic tissue, Notch regulates hepatocyte differentiation. In HCC, Notch1/3 activation promotes cancer stem cell self-renewal, EMT, and metastasis, whereas Notch2 may exert tumor-suppressive effects through cellular proliferation inhibition.

3. Aberrant Expression (Etiological Association): HBV/HCV infections can induce Notch activation, accelerating the progression from hepatic injury to HCC development [21].

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References

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