The Interplay of Programmed Cell Death Networks in Cardiovascular Diseases: Mechanisms and Therapeutic Opportunities.

Programmed cell death (PCD) encompasses multiple regulated processes, including apoptosis, pyroptosis, ferroptosis, and necroptosis. These pathways form an interconnected network that contributes to the pathogenesis of cardiovascular diseases (CVDs), including atherosclerosis and myocardial ischemia-reperfusion injury. This review highlights cell-type-specific PCD signatures, showing that endothelial cells predominantly undergo pyroptosis and ferroptosis, whereas macrophages exhibit multiple PCD modalities and complex pathological crosstalk. Moreover, the review systematically summarizes key regulatory pathways (e.g., Piezo1 [Piezo-type mechanosensitive ion channel component 1]/NLRP3 [NOD-like receptor family pyrin domain containing 3], and Nrf2 [nuclear factor erythroid 2-related factor 2]/HO-1 [heme oxygenase 1]/GPX4 [glutathione peroxidase 4]), as well as multi-target natural compounds (e.g., melatonin and Guizhitongluo Tablet) that show translational promise and advantages in modulating PCD networks. The review also provides critical insights into major bottlenecks in clinical translation, including nonspecific tissue distribution and the lack of pathway-specific biomarkers. Novel solutions, such as cardiomyocyte-specific delivery systems (e.g., CD47-targeted lipid nanoparticles) and validated biomarkers (prostaglandin-endoperoxide synthase 2 [PTGS2] for ferroptosis), are also proposed. Overall, this review advances our understanding of PCD network regulation in CVDs and proposes innovative precision therapeutic strategies that align with the evolving needs of cardiovascular translational medicine.