Novel insights of ferroptosis in atherosclerosis progression

Atherosclerosis (AS) is the principal pathological basis of multiple cardiovascular and cerebrovascular diseases and remains a major cause of morbidity and mortality worldwide. Accumulating evidence indicates that ferroptosis, a form of iron-dependent regulated cell death driven by lipid peroxidation, is intricately involved in the initiation and progression of AS. Aberrant iron accumulation, redox imbalance, and impaired antioxidant defenses contribute to endothelial dysfunction, macrophage activation, vascular smooth muscle cell phenotypic switching, lipid metabolic disturbance, and amplified immune-inflammatory responses, thereby accelerating plaque formation and destabilization. Key regulatory systems, including iron transport pathways, the GSH/GPX4 axis, FSP1-CoQ10 signaling, and mitochondrial iron metabolism, have emerged as critical determinants of ferroptotic susceptibility in vascular cells. Experimental studies further suggest that ferroptosis inhibition can attenuate oxidative injury, reduce inflammatory mediator release, improve lipid metabolic profiles, and stabilize atherosclerotic plaques. This review summarizes the mechanisms governing cellular iron homeostasis and ferroptosis, discusses the multifaceted roles of ferroptosis in the major cellular and molecular events underlying AS progression, and highlights the therapeutic promise of targeting ferroptotic pathways in atherosclerotic disease.