Unlocking Resveratrol's Potential: Targeting Ferroptosis in Atherosclerosis Through MAPK1

Atherosclerosis (AS) is a chronic inflammatory metabolic disorder and a leading cause of cardiovascular diseases. Resveratrol (RSV), a natural polyphenolic phytoestrogen, exhibits anti-atherosclerotic effects by modulating oxidative stress and ferroptosis, yet its key therapeutic targets remain unclear. Using network pharmacology, bioinformatics, machine learning, and molecular docking, we identified core targets and mechanisms of RSV in ferroptosis and anti-atherosclerosis. Experimental validation was performed using ApoE^-/- mouse fed a high-fat diet (HFD) for 12 weeks to establish AS model. We assessed aortic and aortic root plaque formation, serum oxidative stress, and iron levels. By mining online databases, we identified 31 shared targets at the intersection of RSV-AS-Ferroptosis. A PPI network was generated using STRING, and GeneMANIA, GO and KEGG analyses revealed key biological processes and pathways (such as oxidative stress). Employing eight machine learning algorithms, we pinpointed six key targets: MAPK1, IL1B, RELA, HIF1A, SRC, and PTEN. Differential gene docking and molecular docking analyses showed that MAPK1 (-8.8 kcal/mol binding energy) had relatively good affinity. In vivo, RSV treatment reduced aortic lipid plaques, reduced serum GSSG/GSH, SOD, MDA, and iron levels, and significantly downregulated MAPK1 expression in the aortic root. RSV could modulate the ferroptosis pathway through targeting the MAPK1 gene, providing a new theoretical framework for AS prevention and treatment.