Iron metabolism and ferroptosis in cardiovascular diseases: progress in the mechanism and pharmacological intervention

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative damage to membrane lipids, has emerged as a critical player in the pathogenesis of cardiovascular diseases (CVDs). This process is characterized by dysregulated iron homeostasis, redox imbalance, and impaired antioxidant defenses, with key regulatory pathways including the System Xc - -GSH-GPX4 axis, FSP1-CoQ10-ubiquinol axis, and GCH1-BH4-phospholipid axis. Accumulating evidence highlights the pivotal role of ferroptosis in diverse CVDs such as atherosclerosis, myocardial ischemia reperfusion injury, heart failure, cardiomyopathy, aortic dissection, aortic aneurysm, vascular endothelial injury, and calcification- and aging- related CVDs. Studies on the molecular mechanism of ferroptosis have revealed potential targets for the treatment of CVDs, and a large number of studies have reported evidence of drug-mediated ferroptosis and iron metabolism mechanisms intervening in CVDs. This review delves into the latest molecular characteristics of ferroptosis, associated biological processes, and regulatory pathways. Notably, various compounds like iron chelators (e.g., deferoxamine, deferiprone), chloroiodohydroxyquin and its derivatives, antioxidants (e.g., vitamin E, lipoic acid, selenium), Ferrostatin-1 (Fer-1), etc., have demonstrated efficacy in animal studies against CVDs, offering cardiovascular protection. In summary, this review outlines the role of ferroptosis in CVDs, the regulatory effects of relevant drugs (including natural products) on ferroptosis within cardiovascular contexts, aiming to provide valuable insights for CVDs management and the development of novel therapeutics.