Oleanolic Acid Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by Inhibiting Ferroptosis through Targeting PTGS2 as a Key Molecular Node and Activating the AMPK/ACC Signaling Pathway.

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression closely involves ferroptosis. Using high-fat diet-challenged mice and free fatty acid (FFA)-treated HepG2 cells, we demonstrate that oleanolic acid (OA) ameliorates MASLD and suppresses ferroptosis─an effect validated by the ferroptosis activator Erastin. Supported by network pharmacology, mechanistic analyses reveal that OA exerts synergistic efficacy via a dual-axis network. First, molecular docking, cellular thermal shift assay (CETSA), and molecular dynamics (MD) simulations confirm that OA directly binds PTGS2, mitigating lipid peroxidation and inflammatory mediator release. Second, OA activates the AMPK/ACC metabolic signaling pathway, inhibiting ACC through phosphorylation to correct lipid metabolism disorders, and its antiferroptotic effect can be blocked by AMPK inhibitors. This study first elucidates OA's therapeutic mechanism against MASLD via "metabolic correction + oxidative inhibition," outlining a novel strategy for targeting hepatic ferroptosis.