{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T17:38:51Z","timestamp":1791826731018,"version":"4.3.4"},"reference-count":59,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82400681"],"award-info":[{"award-number":["82400681"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp; Translational Med"],"published-print":{"date-parts":[[2026,5]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Metabolic dysfunction\u2013associated steatotic liver disease (MASLD) and advanced fibrotic stages are significant contributors to cirrhosis and liver\u2010related 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We quantified hepatic FGF10 and fibroblast growth factor receptor 2 (FGFR2) expression across fibrosis stages in biopsies from patients with MASLD and mouse models. We then augmented hepatic FGF10 using adeno\u2010associated virus\u2010mediated liver expression or subcutaneous recombinant human FGF10 in carbon tetrachloride (CCl\n 4<\/jats:sub>\n ) and high\u2010fat diet plus CCl\n 4<\/jats:sub>\n \u2010induced advanced fibrosis. Histology, immunohistochemistry, biochemistry, RNA sequencing and primary hepatocytes and hepatic stellate cells (HSCs) assays were used to assess the therapeutic effects and underlying mechanisms.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Hepatic FGF10 and FGFR2 protein expression were significantly reduced at advanced disease stages. Restoring FGF10 led to regression\u2010associated remodelling of established bridging fibrosis, a decrease in inflammatory cytokines and a reduction in hepatocyte apoptosis, even with continued CCl\n 4<\/jats:sub>\n exposure, indicating histologic regression rather than slowed progression. These therapeutic effects required hepatocyte FGFR2, as hepatocyte\u2010specific FGFR2 deletion abolished protection and the associated transcriptional reprogramming of matrix and cytokine networks. In primary hepatocytes, FGF10 activated FGFR2\u2013FGFR substrate 2\u03b1 (\u200cFRS2\u03b1) signalling, increased inhibitory phosphorylation of glycogen synthase kinase 3\u03b2 at Ser9 and suppressed nuclear factor kappa B, thereby lowering transforming growth factor \u03b21 and other cytokines and indirectly limiting HSC activation. The efficacy extended to a high\u2010fat diet plus CCl\n 4<\/jats:sub>\n model of steatohepatitis.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n These findings elucidate a hepatocyte\u2010centric FGF10\u2013FGFR2 axis functioning as an epithelial regulator of inflammation and fibrogenesis. Hepatocyte\u2010targeted reinforcement of FGFR2 signalling, alone or combined with metabolic therapies, represents a translational strategy to reprogram the fibrotic niche and facilitate fibrosis regression\u2010associated architectural remodelling in advanced liver fibrosis.<\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Hepatic FGF10 and FGFR2 decline consistently with fibrosis stage in patient liver biopsies and complementary mouse models.<\/jats:p>\n <\/jats:list-item>\n \n Restoring FGF10 through AAV\u2010Fgf10 or recombinant FGF10 reduces hepatocyte apoptosis, inflammation and extracellular matrix deposition.<\/jats:p>\n <\/jats:list-item>\n \n Hepatocyte FGFR2 is required for FGF10\u2010mediated antifibrotic effects and drives transcriptional reprogramming that limits fibrogenesis.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n 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