Comprehensive Review of Mechanisms and Translational Perspectives on Programmed Cell Death in Vascular Calcification.

Programmed cell death (PCD), a regulated cell death (RCD) subtype essential for physiological homeostasis, encompasses distinct mechanisms including apoptosis, necroptosis, autophagy, ferroptosis, cuproptosis, and pyroptosis. This evolutionarily conserved process critically regulates disease pathogenesis across degenerative disorders, malignancies, fungal infections, and vascular calcification (VC). VC manifests as pathological calcium deposition in cardiovascular tissues, impairing vascular elasticity and hemodynamics. These structural alterations elevate risks of atherosclerotic events, cerebrovascular accidents, and peripheral vascular dysfunction, while concomitantly inducing vital organ hypoperfusion and cardiac overload that predispose individuals to myocardial ischemia, left ventricular hypertrophy, and heart failure. Despite advances in delineating associated signaling networks, the molecular etiology of VC remains elusive, and effective therapeutic interventions are currently lacking. While systematically examining the pathophysiological contributions of both established and novel PCD mechanisms to VC progression, this review incorporates a discussion of cuproptosis as a novel form of PCD, which may serve as a target for atherosclerosis treatment. The inclusion of cuproptosis, alongside other PCD modalities, allows for a more integrated and updated perspective on the complex regulatory networks governing VC. Our objective is to synthesize the current understanding of how these diverse PCD pathways, both classical and emerging, collectively contribute to the disease pathogenesis and to explore the broader therapeutic potential of targeting PCD in VC.