FGF/FGFR signaling in hepatocellular carcinoma: From molecular mechanisms to biomarker-guided therapy.

Hepatocellular carcinoma (HCC) is the predominant histological subtype of primary liver cancer and remains a leading cause of cancer-related mortality because of its molecular heterogeneity, high recurrence rate, and incomplete responses to systemic therapy. Among dysregulated oncogenic networks, fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling contributes to hepatocarcinogenesis, angiogenesis, stromal remodeling, immune escape, and therapeutic resistance. This review critically examines the biological organization and translational implications of FGF/FGFR signaling in HCC, with particular emphasis on the FGF19-KLB-FGFR4 axis and a cautious appraisal of its current translational maturity. FGF2, the FGF8 subfamily, FGF9, and FGF19 drive context-dependent tumor programs shaped by etiology, cirrhosis, stromal interactions, intratumoral heterogeneity, and crosstalk with major oncogenic pathways. Although FGF19-KLB-FGFR4 is the most mature and clinically testable FGF-related therapeutic framework in HCC, selective FGFR4 inhibition is still limited by early-phase clinical evidence, bile-acid-related toxicity, FGFR3/KLB-mediated redundancy, bypass signaling, and acquired resistance. Early clinical data with irpagratinib support the rationale for combining FGFR4 inhibition with immune checkpoint blockade, but definitive validation and reproducible biomarker assays are still needed. Future translation should prioritize prospectively validated biomarker panels, mechanism-based combinations, longitudinal resistance monitoring, and models that recapitulate the cirrhotic, immune-active liver microenvironment.