Iron, lipid peroxidation, and ferroptosis play pathogenic roles in atherosclerosis

Abstract Oxidation of lipids, excessive cell death, and iron deposition are prominent features of human atherosclerotic plaques. While extensive research has established the detrimental roles of lipid oxidation and apoptosis in atherosclerosis development, the involvement of iron in atherogenesis is not yet fully understood. With the emergence of an iron-dependent form of cell death termed ferroptosis, new attention has been brought to the complex inter-play among iron, ferroptosis, and atherosclerosis. Mechanistically, ferroptosis is caused by the lethal accumulation of iron-mediated lipid peroxides. Emerging studies have underscored ferroptosis as a contributor to worsened atherosclerosis. Herein, we review the evidence that oxidative damage and iron overload in the context of atherosclerosis may promote ferroptosis within plaques. Furthermore, we summarize recent findings of lipid peroxidation, thereby potentially ferroptosis, in various plaque cell types—such as endothelial cells, macrophages, dendritic cells, T cells, and vascular smooth muscle cells—across different stages of atherosclerosis. Understanding how these processes influence atherosclerotic plaque progression may permit targeting stage-dependent ferroptosis in each cell population and could provide a rationale for developing cell type–specific intervention strategies to mitigate atherogenic ferroptosis effectively.