Fibroblast Growth Factor Signaling in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is driven by complex molecular networks in which fibroblast growth factor (FGF) signalling plays a central role. FGFs constitute a family of polypeptide ligands that engage FGF receptors (FGFRs), of which FGFR4 is predominantly expressed in hepatocytes. The endocrine ligand FGF19 binds selectively to FGFR4 in concert with the co-receptor β-klotho, regulating bile acid metabolism, glucose homeostasis and hepatocyte proliferation. In HCC, aberrant amplification or overexpression of FGF19 and FGFR4 fosters oncogenic programmes through activation of downstream cascades such as RAS–MAPK, PI3K–AKT and STAT pathways. This axis promotes cell cycle progression, evasion of apoptosis, angiogenesis and epithelial–mesenchymal transition. Crosstalk with the inflammatory microenvironment, notably via IL-6-driven STAT3 activation, further potentiates tumourigenesis and contributes to immune modulation. Clinically, dysregulated FGF19–FGFR4 signalling is associated with aggressive disease, metastasis and resistance to therapies such as multikinase inhibitors. Selective FGFR4 antagonists and pan-FGFR inhibitors are advancing through clinical trials, while combination approaches with epigenetic or immune-targeted agents are emerging to overcome adaptive resistance. A nuanced understanding of FGF signalling dynamics promises improved stratification of HCC patients and the development of personalised therapeutic regimens.

Research from Nature Portfolio

Recent studies have revealed that FGF19 drives a paracrine circuit in which hepatic stellate cells and immune populations secrete IL-6, activating STAT3 in adjacent hepatocytes to promote tumour initiation. Genetic ablation of IL-6 or hepatocyte-specific STAT3, or pharmacological inhibition of JAK-STAT signalling, abolishes FGF19-induced hepatocarcinogenesis while preserving its metabolic functions. This work uncovers the non-cell-autonomous nature of FGF19 oncogenicity and identifies the IL-6/STAT3 axis as a critical mediator and potential therapeutic target in HCC.

Fibroblast Growth Factor Signaling in Hepatocellular Carcinoma publication trend

The graph below shows the total number of articles in fibroblast growth factor signaling in hepatocellular carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Fibroblast Growth Factor 19 (FGF19): An endocrine FGF family member that regulates bile acid and metabolic homeostasis and acts as an oncogenic ligand for FGFR4 in the liver.

Fibroblast Growth Factor Receptor 4 (FGFR4): A receptor tyrosine kinase highly expressed in hepatocytes; activation by FGF19 triggers downstream proliferation and survival pathways.

STAT3 signalling: A transcriptional programme activated by cytokines such as IL-6, promoting cell growth and survival; implicated in the paracrine effects of FGF19 in HCC.

EZH2: A histone methyltransferase and core component of the PRC2 complex; upregulated upon FGFR4 inhibition and implicated in therapy resistance.

YAP signalling: A branch of the Hippo pathway that regulates organ size and tumour growth; repression of YAP contributes to apoptosis in combined FGFR4/EZH2 blockade.

References

1. FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling. Journal of Experimental & Clinical Cancer Research (2023).
2. FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis. EMBO Molecular Medicine (2024).
3. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. Journal of Experimental & Clinical Cancer Research (2017).
4. FGF19–FGFR4 Signaling in Hepatocellular Carcinoma. Cells (2019).
5. Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis. Nature Communications (2017).
6. Fibroblast growth factor 19 expression correlates with tumor progression and poorer prognosis of hepatocellular carcinoma. BMC Cancer (2012).