Fibroblast growth factor 19/15-mediated metabolic regulation supports its drug development potential: a narrative review

This narrative review summarizes the regulation, physiological and pathological functions, and therapeutic development of endocrine fibroblast growth factor 19 (FGF19) in humans and its murine ortholog fibroblast growth factor 15 (FGF15). FGF19/15 refers to the conserved gut-liver endocrine axis, whereas FGF19 and FGF15 are used for human and mouse evidence, respectively. FGF19/15 is mainly induced in ileal enterocytes by bile acid-activated farnesoid X receptor (FXR), enters the portal circulation, and acts on target organs, especially the liver, through the fibroblast growth factor receptor 4 (FGFR4)/β-Klotho (KLB) complex. FGF19/15 regulates bile acid synthesis, glucose metabolism, energy balance, hepatocyte proliferation, and tissue repair through pathways including mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT). The pathway maintains metabolic homeostasis by repressing cholesterol 7 alpha-hydroxylase (CYP7A1), modulating glycogen synthesis and gluconeogenesis, and contributing to thermogenic and systemic energy regulation. These functions support the therapeutic potential of FGF19 analogs for metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis (MASLD/MASH), cholestatic disorders, and type 2 diabetes. However, FGF19/15 also has context-dependent tumor-related effects and can promote hepatocellular carcinoma through FGF19-FGFR4 signaling. Drug development has therefore advanced in two directions: non-tumorigenic FGF19 analogs for metabolic or cholestatic diseases and selective FGFR4 inhibitors for biomarker-selected tumors. Current clinical data remain heterogeneous because of safety concerns, tissue specificity, resistance, and species-dependent interpretation. Future studies should refine biomarkers, optimize tissue-selective drug designs, and evaluate rational combination strategies.