Sesamin attenuates atherosclerosis by alleviating vascular endothelial ferroptosis-related injury via m6A-dependent regulation of SREBF1 expression

Objective This study was designed to elucidate the molecular pathways responsible for anti-atherosclerotic effects of the traditional Chinese medicine formula Yishen Huoxue Huatan, with a focus on its key active component sesamin. Methods Network pharmacology was applied to predict potential targets and pathways associated with the anti-atherosclerotic activity of Yishen Huoxue Huatan. An atherosclerosis model was constructed in ApoE −/− mice treated with sesamin (50 or 100 mg/kg), and endothelial injury was induced in human umbilical vein endothelial cells (HUVECs) using oxidized low-density lipoprotein (ox-LDL). Aortic pathology, lipid profiles, m 6 A RNA methylation levels, iron accumulation, oxidative stress, and ferroptosis-related markers were assessed. Ferrostatin-1 (Fer-1) was used to verify the involvement of ferroptosis in sesamin-mediated endothelial protection. The involvement of the METTL3/SREBF1 axis was further investigated using RT–qPCR, MeRIP–qPCR, mRNA stability assays, and gene-silencing approaches. Results Network pharmacology identified sesamin as a major bioactive constituent associated with atherosclerosis-related and epigenetic regulatory pathways. In ApoE −/− mice, sesamin reduced aortic lipid deposition, alleviated vascular injury, and improved dyslipidemia. In HUVECs, sesamin attenuated ox-LDL–induced endothelial injury, iron overload, lipid peroxidation, and oxidative stress. Fer-1 produced protective effects similar to those of sesamin, supporting the involvement of ferroptosis inhibition in sesamin-mediated endothelial protection. Mechanistically, sesamin downregulated METTL3 expression and reduced m 6 A modification of SREBF1 mRNA, thereby increasing SREBF1 mRNA stability and protein expression. SREBF1 silencing markedly weakened the anti-ferroptotic effects of sesamin, whereas concurrent METTL3 knockdown partially restored this protective phenotype. Conclusion Sesamin upregulates SREBF1 expression by inhibiting METTL3-mediated m 6 A methylation, thereby alleviating ferroptosis-related alterations in vascular endothelial cells and ultimately delaying the progression of atherosclerosis.