The Regulatory Landscape of Ferroptosis and Iron Homeostasis: Pathophysiological Mechanisms and Therapeutic Horizons in Cardiovascular Disease

Ferroptosis is an iron-dependent form of regulated cell death driven by unrestrained lipid peroxidation, morphologically and biochemically distinct from apoptosis, necrosis, and autophagy. It is increasingly recognized as a core pathophysiological mechanism across the full spectrum of cardiovascular diseases, including myocardial ischemia-reperfusion injury, heart failure, atherosclerosis, diabetic cardiomyopathy, and chemotherapy-induced cardiotoxicity. The initiation and progression of ferroptosis are governed by the dysregulation of iron homeostasis, lipid metabolic remodeling, and collapse of antioxidant defense systems, with extensive crosstalk with other regulated cell death modalities in cardiovascular pathophysiology. Preclinical studies have consistently demonstrated that targeting ferroptosis exerts robust cardioprotective effects via multiple mechanisms. However, clinical translation faces key hurdles, including the lack of specific biomarkers, off-target risks, and interindividual heterogeneity in therapeutic response. This review systematically summarizes the regulatory mechanisms of ferroptosis, its causal role in cardiovascular diseases, and the latest advances in targeted therapeutic strategies, with a focus on clinical translation prospects and challenges.