Fibroblast growth factor 10 attenuates advanced liver fibrosis through hepatocyte fibroblast growth factor receptor 2 signalling

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and advanced fibrotic stages are significant contributors to cirrhosis and liver-related mortality, yet no therapies directly target fibrosis in the later stages of the disease. Fibroblast growth factor 10 (FGF10) facilitates epithelial repair, yet its function and epithelial receptor requirements in chronic liver fibrogenesis are unclear. Histology, immunohistochemistry, biochemistry, RNA sequencing and primary hepatocytes and hepatic stellate cells (HSCs) assays were used to assess the therapeutic effects and underlying mechanisms. RESULTS: model of steatohepatitis. CONCLUSIONS: These findings elucidate a hepatocyte-centric FGF10-FGFR2 axis functioning as an epithelial regulator of inflammation and fibrogenesis. Hepatocyte-targeted reinforcement of FGFR2 signalling, alone or combined with metabolic therapies, represents a translational strategy to reprogram the fibrotic niche and facilitate fibrosis regression-associated architectural remodelling in advanced liver fibrosis. KEY POINTS: Hepatic FGF10 and FGFR2 decline consistently with fibrosis stage in patient liver biopsies and complementary mouse models. Restoring FGF10 through AAV-Fgf10 or recombinant FGF10 reduces hepatocyte apoptosis, inflammation and extracellular matrix deposition. Hepatocyte FGFR2 is required for FGF10-mediated antifibrotic effects and drives transcriptional reprogramming that limits fibrogenesis.