Aims:　Nicotine-exacerbated　atherosclerosis　significantly　increases　global　mortality.　Endothelial　cells,　which　line　the　interior　of　blood　vessels,　are　crucial　for　maintaining　vascular　function.　How　nicotine　is　involved　in　vascular　remodeling　in　atherosclerosis　via　modulating　endothelial　dysfunction　remains　unknown.　Materials　and　methods:　Comprehensive　gene　expression　analyses　identified　key　genes　upregulated　in　the　ferroptosis　pathway　in　smoking-exacerbated　atherosclerosis.　Predictive　models　integrating　these　ferroptosis-related　genes　were　constructed　to　differentiate　atherosclerotic　plaques.　Key　findings:　Here,　we　reveal　that　ferroptosis　mediates　nicotine-induced　endothelial　dysfunction,　exacerbating　atherosclerosis.　Mechanistically,　nicotine　elevates　sequestosome　1　(SQSTM1),　leading　to　iron　overload　and　an　increase　in　reactive　oxygen　species　(ROS)　and　the　levels　of　ferroptosis　markers　heme-oxygenase　1　(HMOX1)　and　prostaglandin-endoperoxide　synthase　2　(PTGS2),　contributing　to　ferroptosis　in　endothelial　cells　and　the　aberrant　production　of　inflammatory　factors.　Pharmacological　inhibition　of　ferroptosis　and　normalization　of　iron　levels　by　knocking　down　SQSTM1　mitigate　endothelial　ferroptosis　and　reduce　production　of　pro-inflammatory　factors.　Diagnostically,　human　plasma　levels　of　HMOX1,　SQSTM1,　and　PTGS2　are　elevated　in　smokers　with　atherosclerosis　but　reduce　in　ex-smokers.　Predictive　models,　including　a　support　vector　machine　integrating　these　ferroptosis-related　genes,　effectively　differentiate　between　early-　and　advanced-stage　atherosclerotic　plaques.　Significance:　SQSTM1　upregulation-induced　iron　overload　triggers　endothelial　ferroptosis　in　nicotine-exacerbated　atherosclerosis,　suggesting　excellent　predictive　efficacy　for　atherosclerosis　development　and　potential　for　clinical　applications.　Trial　registration:　This　study　has　been　registered　in　the　Chinese　Clinical　Trial　Registry　(ChiCTR2400083484,　Registration　Date:　April　26,　2024).