Ironing out the details: ferroptosis and its relevance to diabetic cardiomyopathy

Abstract

Ferroptosis is a newly identified myocardial cell death mechanism driven by iron-dependent lipid peroxidation. The presence of elevated intramyocardial lipid levels and excessive iron in diabetic patients suggest a predominant role of ferroptosis in diabetic cardiomyopathy. Since myocardial cell death is a precursor of heart failure and intensive glycemic control cannot abate the increased risk of heart failure in diabetic patients, targeting myocardial cell death via ferroptosis is a promising therapeutic avenue to prevent and/or treat diabetic cardiomyopathy. This review presents updated and comprehensive knowledge on mechanisms underpinning ferroptosis, clarifies several misconceptions about ferroptosis, emphasizes the importance of ferroptosis in diabetes-induced myocardial cell death, and offers valuable approaches to evaluate and target ferroptosis in the diabetic heart. Furthermore, basic concepts and ideas rendered in this review, including glutathione peroxidase-4-independent and mitochondrial mechanisms of ferroptosis, are also critical for investigating ferroptosis in other diabetic organs, as well as non-diabetic and metabolically compromised hearts.