Lycorine ameliorates MASH by targeting ACSL4 to regulate lipid metabolism and inhibit ferroptosis

Metabolic dysfunction-associated steatohepatitis (MASH), a progressive stage of metabolic dysfunction-associated steatotic liver disease (MASLD), has emerged as one of the most prevalent chronic liver diseases worldwide, yet therapeutic options remain limited. In this study, we found that lycorine effectively alleviated MASH both in vitro and in vivo. RNA-seq analysis revealed that lycorine suppressed lipid uptake and mitigated ferroptosis in MASH models. Using drug affinity responsive target stability coupled with mass spectrometry (DARTS-MS), we identified acyl-CoA synthetase long-chain family member 4 (ACSL4) as a direct binding target of lycorine. Mechanistically, lycorine targeted ACSL4 to regulate lipid metabolism and ferroptosis pathways, thereby reducing lipid uptake and accumulation, attenuating lipid peroxidation and ferroptosis, and ultimately ameliorating MASH progression. Collectively, our findings elucidate the precise mechanism and direct target through which lycorine alleviates MASH, strongly suggesting that natural compounds such as lycorine hold promise as candidate therapeutics for MASH.