Hepatoma‐Derived Growth Factor Coordinates STAT3 Pathway and Exosome‐Mediated Intrahepatic Crosstalk to Control Hepatic Steatosis and MASLD

Metabolic dysfunction-associated steatotic liver disease has become a predominant cause of chronic liver disease worldwide and represents a major clinical management challenge owing to the scarcity of effective therapeutic interventions. However, the molecular mechanisms driving MASLD progression remain incompletely understood. Here, we identify hepatoma-derived growth factor (HDGF) as a key regulator that integrates lipogenesis with intrahepatic inflammation in MASLD pathogenesis. Hepatic HDGF deficiency profoundly protects mice from high-fat, high-sucrose diet-induced hepatic steatosis and inflammation. Mechanistically, HDGF promotes lipogenesis and hepatic steatosis by facilitating S6K1-dependent phosphorylation of STAT3 at Ser727. Consistently, pharmacological inhibition of STAT3 by S3I-201 abolishes HDGF-induced 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-STAT3 pathway and exosomal HDGF secretion may represent a potential therapeutic strategy for ameliorating metabolic dysfunction and hepatic inflammation in MASLD and related disorders.