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Objective To explore the roles of iron overload in pro - atherogenic activation of foam cells. Methods RAW264.7 and MOVAS cells were stimulated by oxLDL, ferrimine citrate and deferoxamine respectively. Prussian Blue and Oil Red O staining were used to detect iron deposition and foam cell. CCK-8 test, DHE probe, ELISA, RT-qPCR were performed to detect the cell death rate, reactive oxygen species (ROS) generation, lipid peroxidation molecules [glutathione peroxidase (GSH), glutathione peroxidase 4 (GPX4), malondialdehyde (MDA) content] and the mRNA level of ATP binding cassette transporter A1 (ABCA1), ATP binding cassette transporter G1 (ABCG1), inductible nitris oxide synthase (iNOS), arginase-1 (Arg-1), a-smooth muscle actin (a-SMA), smooth muscle 22 alpha (SM22a), osteopontin (OPN), Interleukin-ip (IL-ip), tumor necrosis factor-a (TNF-a). Results Iron overload could reduced reverse cholesterol transporters (ABCA1 and ABCG1), promote foam cells generation, increased cell death rate, induced the expression of lipid peroxidation molecules (GSH, GPX4, MDA), and promoted pro-inflammatory M1 marker of macrophage and synthetic marker expression of vascular smooth muscle cell (VSMC) and inflammatory cytokines (IL-ip, TNF-a). Conclusion Iron overload promotes the generation of foam cells derived from macrophages and smooth muscle cells and transform them into pro - atherosclerotic phenotype, aggravates cell lipid peroxidation and inflammatory reaction, which contributes to the progress of atherosclerosis. [ABSTRACT FROM AUTHOR]