Antioxidant proteins can be potential targets in ameliorating ferroptosis in diabetic cardiomyopathy: a literature review

Abstract

Diabetic cardiomyopathy (DCM) is one of the cardiovascular complications of diabetes mellitus, which is different from myocardial damage caused by coronary ischemia, hypertension, and valvular disease. DCM lacks distinct clinical manifestations in its early stages, and current therapeutic approaches primarily focus on symptomatic management. Emerging evidence indicates that even with optimized glycemic regulation, the pathophysiological progression of DCM remains unmitigated. Exploring the pathogenic mechanism of DCM is the focus and hotspot of current research. Ferroptosis, an iron-dependent form of regulatory cell death, is crucial in DCM myocardial damage. Dysfunctional antioxidant defense system, increased oxidative stress, and elevated reactive oxygen species are the key mechanisms of ferroptosis in DCM. Thus, this review innovatively takes antioxidant proteins as the entry point, and for the first time systematically summarizes the molecular mechanism of antioxidant proteins to improve DCM by regulating the ferroptosis pathway, and summarizes the therapeutic strategy of medications to enhance ferroptosis in DCM by targeting the expression of antioxidant proteins, to explore the potential targets to improve ferroptosis in DCM, to provide a new perspective for the study of delaying the progression of DCM.

Keywords: Antioxidant proteins; Diabetic cardiomyopathy; Ferroptosis; Oxidative stress; Therapy.

Fig. 1

Ferroptosis mechanism. ACSL4, Acyl-CoA Synthetase Long Chain Family Member 4; ALOX15, Arachidonate 15-Lipoxygenase; CQ10, Coenzyme Q10; CQ10H2, Coenzyme Q10H2; DMT1, Divalent Metal Transporter 1; DHODH, Dihydroorotate Dehydrogenase; FSP1, Ferroptosis Suppressor Protein1; FTL, Ferritin Light Chain; FTH1, Ferritin Heavy Chain 1; Glu, Glutamic Acid; Gln, Glutamine; GSH, Glutathione; GSSH, Glutathione Sulfide; GPX4, Glutathione Peroxidase 4; LPCAT3,Lysophosphatidylcholine Acyltransferase 3; NADP⁺, Nicotinamide Adenine Dinucleotide Phosphate - Oxidized Form; NADPH, Nicotinamide Adenine Dinucleotide Phosphate - Reduced Form; NCOA4, Nuclear Receptor Coactivator 4; OXPHOS, Oxidative Phosphorylation; PUFA, Polyunsaturated Fatty Acid; PUFA-CoA, Polyunsaturated Fatty Acid-Coenzyme A; PUFA-PL, Polyunsaturated Fatty Acid-Phospholipid; PUFA-OOH, Polyunsaturated Fatty Acid Hydroperoxide; PUFAs-OH, Polyunsaturated Fatty Acids; PUFAs-OOH, Polyunsaturated Fatty Acids Hydroperoxides; STEAP3, Six-transmembrane Epithelial Antigen of the Prostate 3; TAC cycle, Tricarboxylic Acid Cycle; α-kG, α-Ketoglutarate; VDAC, Voltage Dependent Anion Channel. The figure was created by Figdraw. ┴, suppress;↓, activate

Fig. 2

The role of antioxidant proteins in ferroptosis in DCM. CoQ10, Coenzyme Q10; CoQ10H2, Coenzyme Q10H2; DCM, Diabetic Cardiomyopathy; FSP1, ferroptosis suppressor protein1; GSH, Glutathione; GSSH, Glutathione Sulfide; GPX4, Glutathione Peroxidase 4; HO-1, Heme Oxygenase-1; Nrf2, Nuclear Factor Erythroid 2-related Factor 2; ROS, Reactive Oxygen Species. The figure was created by Figdraw. ┴, suppress;↓, activate

Fig. 3

Targeting antioxidant proteins ameliorates ferroptosis in DCM. DCM, Diabetic Cardiomyopathy; FSP1, ferroptosis suppressor protein1; GPX4, Glutathione Peroxidase 4; Nrf2, Nuclear Factor Erythroid 2-related Factor 2; ROS, Reactive Oxygen Species. The figure was created by Figdraw. ┴, suppress;↓, activate