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However, the molecular mechanisms driving MASLD progression remain incompletely understood. Here, we identify hepatoma\u2010derived growth factor (HDGF) as a key regulator that integrates lipogenesis with intrahepatic inflammation in MASLD pathogenesis. Hepatic HDGF deficiency profoundly protects mice from high\u2010fat, high\u2010sucrose diet\u2010induced hepatic steatosis and inflammation. Mechanistically, HDGF promotes lipogenesis and hepatic steatosis by facilitating S6K1\u2010dependent phosphorylation of STAT3 at Ser727. Consistently, pharmacological inhibition of STAT3 by S3I\u2010201 abolishes HDGF\u2010induced lipogenic gene expression and hepatic steatosis in mouse models. Importantly, phosphorylation of HDGF at Ser165 is essential for its exosomal secretion from hepatocytes, thereby triggering proinflammatory macrophage activation. In humans, both serum and hepatic levels of HDGF are elevated and positively correlated with MASLD progression. Together, these findings uncover a mechanism that couples hepatic lipogenesis to intrahepatic macrophage activation, driving both steatosis and inflammation in MASLD. Targeting the HDGF\u2010STAT3 pathway and exosomal HDGF secretion may represent a potential therapeutic strategy for ameliorating metabolic dysfunction and hepatic inflammation in MASLD and related disorders.<\/jats:p>","DOI":"10.1002\/advs.202523964","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T07:37:02Z","timestamp":1777621022000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hepatoma\u2010Derived Growth Factor Coordinates STAT3 Pathway and Exosome\u2010Mediated Intrahepatic Crosstalk to Control Hepatic Steatosis and MASLD"],"prefix":"10.1002","volume":"13","author":[{"given":"Jian","family":"Wen","sequence":"first","affiliation":[{"name":"Department of General Surgery (Hepatobiliary Surgery) Biliary\u2010Pancreatic Center The Affiliated Hospital Southwest Medical University  Luzhou Sichuan China"},{"name":"Metabolic Hepatobiliary and Pancreatic Diseases Key Laboratory 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