Ganoderic acid A alleviates metabolic dysfunction-associated fatty liver disease through attenuating steatosis and cellular apoptosis by targeting acetyl-CoA carboxylase.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global metabolic epidemic with no specific effective therapy, characterized by hepatic steatosis and excessive hepatocyte apoptosis. This study explored the protective effects and mechanisms of Ganoderic acid A (GA-A) against MASLD. In high-fat diet (HFD)-fed mice and palmitic acid (PA)-stimulated HepG2 cells, GA-A notably relieved hepatic steatosis, liver injury, lipid metabolic disorders and hepatocyte apoptosis. Acetyl-CoA carboxylase (ACC) was identified as a direct target of GA-A via protein microarray, molecular docking, SPR, CETSA and Co-IP assays. Mechanistically, GA-A activated the AMPK-ACC pathway and suppressed ACC activity. Application of the ACC inhibitor ND646 and ACC silencing partially abrogated GA-A's therapeutic effects, confirming both ACC-dependent and independent actions. Collectively, GA-A directly targets ACC to ameliorate MASLD, indicating its potential as a promising candidate drug for this metabolic liver disease.