Epigenetic regulation and post-translational modifications of ferroptosis-related factors in cardiovascular diseases

Abstract

As an important element of the human body, iron participates in numerous physiological and biochemical reactions. In the past decade, ferroptosis (a form of iron-dependent regulated cell death) has been reported to contribute to the pathogenesis and progression of various diseases. The stability of iron in cardiomyocytes is crucial for the maintenance of normal physiological cardiac activity. Ferroptosis has been detected in many cardiovascular diseases (CVDs), including coronary heart disease, myocardial ischemia-reperfusion injury, heart failure, and chemotherapy-induced myocardial damage. In cardiomyocytes, epigenetic regulation and post-translational modifications regulate the expression of ferroptosis-related factors, maintain iron homeostasis, and participate in the progression of CVDs. Currently, there is no detailed mechanism to explain the relationship between epigenetic regulation and ferroptosis in CVDs. In this review, we provide an initial summary of the core mechanisms of ferroptosis in cardiomyocytes, with first focus on the epigenetic regulation and expression of ferroptosis-related factors in the context of common cardiovascular diseases. We anticipate that the new insights into the pathogenesis of CVDs provided here will inspire the development of clinical interventions to specifically target the active sites of these factors, reducing the harmfulness of ferroptosis to human health.

Keywords: Cardiovascular diseases; Epigenetic regulation; Ferroptosis; Post-translation modification.

Fig. 1

Mechanism of iron homeostasis and ferroptosis occurrence. (By Figdraw.) In cardiomyocytes, iron uptake is dependent on the endocytosis of TF bound to TFR1. Excess iron is either bound to FTH or exported by FPN; iron can be released by ferritinophagy. An excessive LIP accumulates within cells when iron homeostasis is disrupted, leading to overactivation of the Fenton reaction. AA/AdA-PE undergoes iron-dependent lipid autoxidation or peroxidation through the Fenton reaction leading to the formation of PLOOH that eventually destroy membrane integrity and induce ferroptosis. TF, transferrin; TFR1,transferrin receptor protein 1;STEAP3, metalloreductase STEAP3; DMT1, divalent metal transporter 1; AA, arachidonic acid; AdA, adrenic acid; AA-CoA, arachidonic coenzyme; AdA-PE, adrenic acid-phosphatidylethanolamines; LPCAT3, lysophosphatidylcholine acyltransferase 3; PLOOH, phospholipid hydroperoxides LIP, labile iron pool; SLC39A14, solute carrier family 39 member 14 (ZIP14); FPN, ferroportin; FTH, ferritin; NCOA4, nuclear receptor coactivator 4

Fig. 2

Regulatory mechanisms of ferroptosis in CVDs. (By Figdraw.) Harmful lipid peroxides are eliminated by intracellular antioxidant systems. The production of ROS is not always effectively balanced by the antioxidant system. There are three major regulatory pathways regulate ferroptosis in cardiovascular diseases: the xCT System, the Xc-GSH-GPX4 axis, and the FSP1-CoQ-NADPH pathway. SLC7A11, subunit solute carrier family 7 member 11; Glu, glutamate; Gly, glycine; GSH, glutathione; GSSG, oxidized glutathione; GPX4, glutathione peroxidase 4; GSR, glutathione-disulfide reductase, Nrf2, nuclear factor-erythroid 2-related factor 2; CoQ10, coenzyme Q10; FSP1, ferroptosis suppressor protein 1; NADPH, nicotinamide adenine dinucleotide phosphate; CoQH2, ubiquinol; PUFAs-OH, lipid alcohols; PUFAs-OOH, lipid hydroperoxides; ROS, reactive oxygen species