BACKGROUND: Atherosclerosis is a leading factor in the development of several cardiovascular conditions, including ischemic heart disease, stroke, and peripheral vascular disease. A defining characteristic of atherosclerosis is the formation of macrophages and vascular smooth muscle cells (VSMCs)-derived foam cells in plaques. Angioplasty can effectively remove atherosclerotic plaque, while it may lead to restenosis. A crucial pathological feature of restenosis is neointimal formation, which is driven by the phenotypic change, growth, and migration of VSMCs. Nonetheless, there are only a handful of effective strategies. Kadsura coccinea is a folk Chinese herb mainly used to treat rheumatism, chronic gastritis, bruises, and dysmenorrhea. Isovaleroylbinankadsurin A (ISBA), isolated from Kadsura coccinea roots, is a dibenzocyclooctadiene lignan that has recently been shown to be beneficial for myocardial ischemia-reperfusion injury. However, its protective effects on atherosclerosis and restenosis remain unknown. PURPOSE: To investigate the effects and related mechanisms of ISBA on atherosclerosis and restenosis. METHODS: Foam cells were induced by ox-LDL in vitro, and a high-fat diet was administered to ApoE RESULTS: We found for the first time that ISBA could significantly alleviate atherosclerosis and restenosis. Mechanistically, ISBA inhibited lipid accumulation and reduced foam cell formation through the activation of LXRα/ABCA1 signaling pathway, which contributed to preventing atherosclerosis. In addition, ISBA could also suppress the phenotypic switch, proliferation, and migration of VSMCs through repressing TGF-β1/ERK1/2/CTGF and FHL1/ERK1/2/CTGF signaling pathways, thereby mitigating neointimal formation and restenosis. CONCLUSION: This study offers a groundbreaking and expanded exploration of the pharmacological effects of ISBA. ISBA may be a novel therapeutic drug to prevent atherosclerosis and restenosis.