FGF19 in Solid Tumors: Molecular Mechanisms, Metabolic Reprogramming, and Emerging Therapeutic Opportunities

Fibroblast growth factor 19 (FGF19), the human orthologue of murine FGF15, is an endocrine FGF that signals through the FGFR4-β-Klotho receptor complex to regulate bile acid synthesis, glucose and lipid metabolism, and thermogenesis. Beyond its physiological role in metabolic homeostasis, aberrant expression of FGF19 has been increasingly implicated in the initiation and progression of solid tumors. Mechanistically, FGF19 drives signaling cascades that sustain proliferation, invasion, and metabolic reprogramming, while also promoting epithelial-mesenchymal transition, angiogenesis, and immunosuppression to facilitate metastasis. These pleiotropic activities highlight FGF19 as a compelling therapeutic target, and several FGFR4-directed inhibitors have entered clinical evaluation. However, challenges remain, including on-target toxicities, limited selectivity and adaptive resistance. In this review, discuss the molecular mechanisms by which FGF19 shapes tumor biology, evaluate the current status of therapeutic strategies targeting the FGF19-FGFR4 axis, and explore future opportunities such as rational drug combinations and metabolic intervention. A deeper understanding of the interplay between FGF19 signaling, the tumor microenvironment and systemic metabolism will be essential to unlock its potential for precision oncology.