The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

Abstract

The death of terminally differentiated cardiomyocytes is an important pathogenic contributor to the development of several forms of cardiovascular disease. Ferroptosis is a newly characterized form of regulated cell death driven by iron-dependent lipid peroxidation and linked to cardiovascular disease. Ferroptosis involves various metabolic processes, including iron, lipid and glutathione metabolism. Both in vitro and in vivo evidence supports the pathophysiological role of ferroptosis in myocardial ischaemia–reperfusion injury, anthracycline-mediated cardiotoxicity, sepsis‑induced heart injury, hypertrophic cardiomyopathy and diabetic cardiomyopathy. Targeting ferroptosis with specific inhibitors might provide new therapeutic opportunities for previously untreatable cardiovascular conditions. The maintenance of iron homeostasis is essential for proper cardiac function. A growing body of evidence suggests that iron imbalance is the common denominator in many subtypes of cardiovascular disease. In the past 10 years, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process that mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischaemia–reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia and diabetic cardiomyopathy. Therefore, a thorough understanding of the mechanisms involved in the regulation of iron metabolism and ferroptosis in cardiomyocytes might lead to improvements in disease management. In this Review, we summarize the relationship between the metabolic and molecular pathways of iron signalling and ferroptosis in the context of cardiovascular disease. We also discuss the potential targets of ferroptosis in the treatment of cardiovascular disease and describe the current limitations and future directions of these novel treatment targets. Since the discovery of ferroptosis a decade ago, this iron-dependent form of regulated cell death has been implicated in the pathogenesis of cardiovascular disease. In this Review, Fudi Wang and colleagues discuss the link between the metabolic pathways of iron signalling and ferroptosis in the context of the cardiovascular system and describe the potential of ferroptosis inhibitors in the treatment of cardiovascular disease.