Ferroptosis Is a Potential Novel Diagnostic and Therapeutic Target for Patients With Cardiomyopathy

Abstract

Cardiomyocyte death is a fundamental progress in cardiomyopathy. However, the mechanism of triggering the death of myocardial cells remains unclear. Ferroptosis, which is the nonapoptotic, iron-dependent, and peroxidation-driven programmed cell death pathway, that is abundant and readily accessible, was not discovered until recently with a pharmacological approach. New researches have demonstrated the close relationship between ferroptosis and the development of many cardiovascular diseases, and several ferroptosis inhibitors, iron chelators, and small antioxidant molecules can relieve myocardial injury by blocking the ferroptosis pathways. Notably, ferroptosis is gradually being considered as an important cell death mechanism in the animal models with multiple cardiomyopathies. In this review, we will discuss the mechanism of ferroptosis and the important role of ferroptosis in cardiomyopathy with a special emphasis on the value of ferroptosis as a potential novel diagnostic and therapeutic target for patients suffering from cardiomyopathy in the future.

Keywords: cardiac damage; cardiomyopathy; ferroptosis; heart failure; regulated necrosis.

FIGURE 1

The mechanism of ferroptosis in cell. Amino acid metabolism, which can be affected by GSH consumption and reduced activity and availability of GPX4, iron metabolism, lipid peroxidation metabolism, the high concentration of glutamic acid outside the cell, etc. are strongly implicated in the mechanism of ferroptosis. Homocysteine is converted to cystathionine under the catalysis of the cystathionine b-synthase (CBS), and in the final step, cystathionine is converted to cysteine under the action of the corresponding cystathionine g-lyase in the reverse trans-sulfurylation pathway, which can help maintain homeostasis of intracellular cysteine level and subsequently reduce the sensitivity to ferroptotic cell death. The sec-tRNA and CoQ10 produced in the mevalonate pathway can also affect ferroptosis. SLC7A11, the glutamate/cystine antiporter solute carrier family 7 member 11; SLC3A2, the glutamate/cystine antiporter solute carrier family 3 member 2; GSL, glutaminase; Glu, glutamate; Gln, glutamine; GCLC, glutamate-cysteine ligase; GSS, glutathione synthetase; Gly, glycine; GSH, glutathione; GPX4, glutathione peroxidases 4; GR, glutathione reductase; CBS, cystathionine b-synthase; CTH, ceramide trihexoside; Met, Methionine; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; LOXs, lipoxygenases; DMT1, divalent metal transporter 1; ROS, reactive oxygen species; IPP, isopentenyl pyrophosphate; HMGCR, HMG-CoA reductase.