Targeting Ferroptosis and Pyroptosis in Cardiovascular Diseases: Mechanisms and Therapeutic Implication

Cardiovascular diseases (CVDs) remain the leading global cause of morbidity and mortality. Lipid-lowering, anti-inflammatory, and antioxidant strategies improve clinical outcomes but only partly prevent cardiomyocyte loss and remodeling. Emerging evidence identifies ferroptosis, an iron-dependent lipid peroxidation pathway, and pyroptosis, an inflammasome-driven inflammatory cell-death program, as central drivers of myocardial injury, vascular dysfunction, and heart failure (HF) progression. These death modes are mechanistically interconnected: lipid peroxidation and mitochondrial ROS promote NLRP3 inflammasome activation, while gasdermin-mediated cytokine release disrupts iron homeostasis and accelerates oxidative injury. We synthesize current knowledge on ferroptosis–pyroptosis crosstalk in ischemia-reperfusion injury, HF, and atherosclerosis, emphasizing metabolic-immune coupling through GPX4, ACSL4, NLRP3, and GSDMD. We highlight natural products like quercetin, paeoniflorin, and curcumin as dual-pathway regulators, activating Nrf2-GPX4 and suppressing inflammasomes. Advancing ferroptosis–pyroptosis strategies needs clear intervention timing, better compound availability, and more translational research. Dual blockade of oxidative and inflammatory cell death offers promise for precise cardiovascular therapy.