Ferroptosis in arterial atherosclerosis: mechanistic hypotheses, cell type specific vulnerabilities, translational biomarkers, and therapeutic opportunities

Despite significant progress in lipid-lowering and anti-thrombotic therapies, atherosclerosis remains a leading cause of myocardial infarctions and ischemic strokes. Residual risk persists, often linked to sustained vascular inflammation, oxidative stress, and plaque instability—processes that converge on lipid peroxidation pathways within the arterial wall.

Ferroptosis, an iron-dependent form of regulated cell death, occurs when antioxidant defenses fail, leading to toxic accumulation of phospholipid peroxides. Atherosclerotic plaques provide a permissive microenvironment rich in oxidized lipids, redox-active iron, inflammatory mediators, and hypoxia, suggesting ferroptosis may contribute to endothelial barrier dysfunction, macrophage foam cell death, vascular smooth muscle cell loss, and necrotic core expansion.

However, current understanding is constrained by operational definition inconsistencies, reliance on non-specific oxidative stress markers, and insufficient validation in human plaques. This review systematically synthesizes knowledge on ferroptosis in arterial atherosclerosis, incorporating core pathway dynamics—iron homeostasis, polyunsaturated phospholipid metabolism, and lipid peroxide detoxification via systems like Xc–GPX4—alongside parallel protective axes.

It evaluates cell-type-specific vulnerabilities across disease stages, highlighting how disturbed flow, dyslipidemia, metabolic disorders, and innate immune signaling modulate ferroptosis susceptibility and plaque phenotype.