Ferroptosis in diabetic cardiomyopathy: from its mechanisms to therapeutic strategies

Abstract

Diabetic cardiomyopathy (DCM) is defined as structural and functional cardiac abnormalities in diabetes, and cardiomyocyte death is the terminal event of DCM. Ferroptosis is iron-dependent oxidative cell death. Evidence has indicated that iron overload and ferroptosis play important roles in the pathogenesis of DCM. Mitochondria, an important organelle in iron homeostasis and ROS production, play a crucial role in cardiomyocyte ferroptosis in diabetes. Studies have shown some anti-diabetic medicines, plant extracts, and ferroptosis inhibitors might improve DCM by alleviating ferroptosis. In this review, we systematically reviewed the evidence of ferroptosis in DCM. Anti-ferroptosis might be a promising therapeutic strategy for the treatment of DCM.

Keywords: diabetic cardiomyopathy; ferroptosis; iron metabolism; mitochondria; therapy.

Figure 1

The role of ferroptosis in the pathogenesis of DCM. Diabetes or high glucose may cause iron overload, mitochondria disorder, increased NCOA4-mediated ferritinophagy, and an impaired anti-oxidative Nrf2/GPX4 pathway in cardiomyocytes, which all contribute to increased lipid peroxidation and ferroptosis. Ferroptosis inhibitors Fer-1 and Lip-1, anti-diabetic medicine canagliflozin, and the plant extract sulforaphane all exhibit anti-ferroptotic effects in DCM by suppressing lipid peroxidation, activating Nrf2 and promoting Xc-/GSH/GPX4 axis separately. TF, transferrin; TfR1, transferrin 1 receptor; DMT1, divalent metal transporter 1; ZIP, Zrt-, Irt-like Proteins; Nrf2, nuclear factor erythroid 2-related factor 2; NCOA4, nuclear receptor coactivator 4; GSH, glutathione; GPX4, glutathione peroxidase 4; L/TTCC, L/T-type calcium channel; FtMt, mitochondrial ferritin; ROS, reactive oxygen species; Fer-1, ferrostatin–1; Lip-1, liproxstatin–1. The figure was created by Figdraw.