Abstract
Cardiovascular diseases (CVDs) remain one of the leading causes of morbidity and mortality worldwide, with cardiomyocyte death playing an important role in myocardial injury, pathological cardiac remodeling, and the progression of heart failure. Programmed cell death (PCD), including apoptosis, pyroptosis, ferroptosis, cuproptosis, and disulfidptosis, plays an essential role in maintaining cellular homeostasis; however, its aberrant activation or dysregulation can contribute to cardiovascular injury and disease progression. Increasing evidence indicates that these PCD pathways are not independent but form a complex regulatory network through shared mechanisms, including mitochondrial dysfunction, oxidative stress, inflammatory activation, and metabolic imbalance, thereby contributing collectively to the development and progression of CVDs. Therefore, targeting PCD-related pathways has emerged as a promising therapeutic strategy. Natural products and their bioactive constituents can exert cardioprotective effects by regulating PCD-related signaling networks through multiple targets and pathways, thereby alleviating cardiomyocyte death, oxidative stress, inflammation, and cardiac dysfunction. Representative bioactive compounds, including salvianolic acid B, resveratrol, quercetin, and astragaloside IV, have demonstrated potential to modulate PCD-related signaling pathways in experimental models of CVDs. This review summarizes the molecular mechanisms and pathological roles of apoptosis, pyroptosis, ferroptosis, cuproptosis, and disulfidptosis in CVDs, elucidates the regulatory crosstalk among different PCD pathways, and systematically reviews the research progress on the cardioprotective effects of natural products and their bioactive constituents through targeting PCD. In conclusion, natural products targeting dysregulated PCD pathways may represent a promising multi-target therapeutic strategy for cardiovascular protection; however, current evidence is derived predominantly from preclinical studies, and further in-depth mechanistic investigations and high-quality clinical studies are warranted to validate their therapeutic potential and clinical translational value.