Therapeutic targeting of the AMPK-Has1 complex formation ameliorates metabolic dysfunction-associated steatohepatitis in mice

<b>Rationale:</b> Metabolic dysfunction-associated steatohepatitis (MASH) is a severe liver disease with limited therapeutic options. This study aimed to investigate the protective effects of elemicin (Ele) against MASH and its underlying mechanisms, focusing on the interaction between AMP-activated protein kinase (AMPK) and hyaluronan synthase 1 (Has1). <b>Methods:</b> HFHC diet-induced MASH mouse models and palmitic acid/oleic acid (PO)-treated primary hepatocytes were used. Transcriptomic and lipidomic analyses, immunohistochemistry, western blotting, and molecular docking were employed to assess gene expression, lipid metabolism, inflammation, and fibrosis. Interactions between Ele, AMPK, and Has1 were validated <i>via</i> SPR, Co-IP, and CETSA. <b>Results:</b> Ele significantly ameliorated hepatic steatosis, inflammation, and fibrosis in MASH mice. Systematic profiling of transcriptomic and lipidomic landscapes reveals that Has1-mediated lipid metabolism is strongly correlated with MASH severity in dietary mouse models. Using loss-of-function studies, liver-specific inhibition of Has1 ameliorates hepatic steatosis, inflammation and fibrosis <i>in vivo</i> and <i>in vitro</i>. The anti-MASH effects of Ele are largely dependent on interrupting the formation of AMPK/Has1 complex. Furthermore, Ele normalized hepatic phospholipid profiles, particularly increasing phosphatidylethanolamine to improve mitochondrial function. <b>Conclusions:</b> Ele protects against MASH by interrupting AMPK/Has1 interaction, regulating lipid metabolism, and restoring mitochondrial function. Collectively, these findings highlight Ele as a potential therapeutic agent and Has1 as a novel target for MASH treatment.