Cell-Type-Specific Regulation of Ferroptosis in Atherosclerosis: Mechanisms and Therapeutic Potential of Natural Products.

摘要

Ferroptosis is a regulated form of cell death in which disturbed iron metabolism, accumulation of peroxidized membrane lipids, and insufficient glutathione peroxidase 4 (GPX4) activity converge to injure vascular cells. In atherosclerosis, its effects are highly dependent on cellular context rather than being uniform across the vessel wall. In macrophages, ferroptotic injury strengthens inflammatory signaling and contributes to necrotic-core growth; in vascular smooth muscle cells, it impairs mitochondrial fitness, contractile phenotype maintenance, and extracellular matrix support, thereby weakening the fibrous cap; and in endothelial cells, it disrupts redox homeostasis and barrier function, facilitating lipid entry and early lesion formation. This review synthesizes recent advances in the molecular regulation of ferroptosis in atherosclerosis and emphasizes how its functional consequences differ among plaque-resident cell types. We also discuss natural products and traditional Chinese medicine-derived compounds as promising modulators of ferroptosis-related pathways, owing to their multi-target actions and potential suitability for chronic vascular intervention. By connecting mechanistic evidence with therapeutic implications, we propose that cell-type-aware regulation of ferroptosis, rather than indiscriminate suppression, may offer a rational strategy for plaque stabilization and cardiovascular risk reduction. Significance: Ferroptosis is increasingly recognized as an important contributor to atherosclerosis, but its vascular effects vary substantially among endothelial cells, macrophages, and vascular smooth muscle cells. This review analyzes how cell-specific differences in iron handling, lipid peroxidation, and antioxidant defenses shape plaque initiation, inflammatory progression, and fibrous-cap stability. We further summarize evidence that natural compounds can modulate these ferroptosis-related networks and restore redox and cellular homeostasis. By linking vascular cell heterogeneity with natural product-based intervention strategies, this review provides a mechanistic and translational framework for more precise targeting of ferroptosis in atherosclerosis.