Ferroptosis in Cardiovascular Disease: Mechanisms and Pharmacological Targets
Author
Devunuri Sravani, Polepaka Keerthi, Verpula Nikhitha, M. Rakesh, Syeda Nishat Fathima
Abstract
Loss of cardiomyocytes, endothelial cells, and vascular smooth muscle cells underlies myocardial infarction, heart failure, cardiomyopathies, and vascular disease. For decades, apoptosis and necrosis dominated explanations for this loss, but the recognition of ferroptosis, an iron-dependent form of regulated cell death driven by uncontrolled peroxidation of membrane phospholipids, has opened a new mechanistic and therapeutic perspective. The heart is especially exposed to this process because cardiomyocytes are rich in mitochondria, depend on a continuous supply of iron for oxidative metabolism, and operate under high oxidative load. This review summarizes the molecular machinery of ferroptosis, including iron handling, polyunsaturated phospholipid metabolism, and the glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and related defense systems. It then examines evidence for ferroptosis in ischemia–reperfusion injury, heart failure, anthracycline cardiotoxicity, diabetic and septic cardiac injury, iron-overload cardiomyopathy, and atherosclerosis. Finally, it evaluates pharmacological strategies, including radical-trapping antioxidants, iron chelators, inhibitors of lipid-remodeling enzymes, and activators of endogenous defenses, with attention to pharmacokinetic limitations, biomarker needs, and safety concerns such as cardiac iron deficiency and tumor-protective effects in cardio-oncology. Ferroptosis is a promising but still incompletely validated target, and rigorous translational work will be required to move inhibitors from experimental models to patients.
Keywords
ferroptosis; lipid peroxidation; iron metabolism; GPX4; myocardial ischemia–reperfusion; heart failure; cardiotoxicity; pharmacological targets
Full Text:
References
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