Compared with normoferremic ApoE−/− mice, atherosclerosis is profoundly aggravated in iron-loaded ApoE−/− FPNwt/C326S mice, demonstrating that non-transferrin-bound iron (NTBI)-triggered iron overload aggravates atherosclerosis and reveals a causal link between NTBI and the progression of atherosclerotic lesions. Here, APOE is linked to atherosclerosis.