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

Tianqing Zhang,1 Sijie Xiao,2 Yanfu Xia,3 Kun Chen,1 Honglan Liu,1 Ping Zhang,1 Li Luo1 1Department of Cardiology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, 415003, People’s Republic of China; 2Department of Ultrasound, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, 415003, People’s Republic of China; 3Department of Pathology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, 415003, People’s Republic of ChinaCorrespondence: Ping Zhang, Email 359138850@qq.com Li Luo, Email ilouldh@163.comAbstract: 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.Keywords: ferroptosis, iron homeostasis, lipid peroxidation, cardiovascular diseases, myocardial injury, antioxidant therapy, GPX4, Nrf2, heart failure, ischemia–reperfusion injury, atherosclerosis, therapeutic targeting