Multifaceted cell death in atherosclerosis: Mechanisms, pathological impact, and therapeutic targeting.

Atherosclerosis (AS) is a chronic inflammatory vascular disease associated with aging, the initiation and progression of which is closely related to multiple cell death pathways. This review systematically elucidates the specific activation mechanisms and pathological contributions of ferroptosis, pyroptosis, apoptosis, autophagic cell death, necroptosis, NETosis, cuproptosis, parthanatos, and PANoptosis in vascular endothelial cells (VECs), macrophages, vascular smooth muscle cells (VSMCs), and neutrophils. Collectively, they drive core plaque necrosis, thinning of the fibrous cap, exacerbated inflammation, and thrombosis, ultimately precipitating acute clinical cardiovascular and cerebrovascular events. In addition, therapeutic strategies targeting these pathways are summarized. In-depth understanding of the effects and mechanisms of different forms of cell death in different types of cells would open doors to developing safe and effective interventions against AS. In summary, the progression of AS is driven by the parallel or sequential activation of multiple programmed cell death pathways in different vascular cells; systematically targeting these pathways holds promise as a new strategy to stabilize plaques and prevent acute events.