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.