Ferroptosis and ferritinophagy in diabetes complications

Abstract

Background: With long-term metabolic malfunction, diabetes can cause serious damage to whole-body tissue and organs, resulting in a variety of complications. Therefore, it is particularly important to further explore the pathogenesis of diabetes complications and develop drugs for prevention and treatment. In recent years, different from apoptosis and necrosis, ferroptosis has been recognized as a new regulatory mode of cell death and involves the regulation of nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy. Evidence shows that ferroptosis and ferritinophagy play a significant role in the occurrence and development of diabetes complications.

Scope of review: we systematically review the current understanding of ferroptosis and ferritinophagy, focusing on their potential mechanisms, connection, and regulation, discuss their involvement in diabetes complications, and consider emerging therapeutic opportunities and the associated challenges with future prospects.

Major conclusions: In summary, ferroptosis and ferritinophagy are worthy targets for the treatment of diabetes complications, but their complete molecular mechanism and pathophysiological process still require further study.

Keywords: Diabetes complications; Ferritinophagy; Ferroptosis; Mitochondria.

Figure 1

Three mechanisms of ferroptosis and the relationship between ferroptosis and ferritinophagy. The regulation mechanism of ferroptosis is mainly related to the regulation of iron metabolism, GSH and GPX4, and peroxide. The association between ferritinophagy and ferroptosis is mediated by NCOA4. Intracellular ferritin is transported to autophagy lysosomes for degradation and release of free iron, which eventually leads to ferroptosis. TFR, transferrin receptor; STEAP3, the six-transmembrane epithelial antigen of the prostate 3; DMT1, divalent metal transporter 1; ROS, reactive oxygen species; NCOA4, nuclear receptor co-activator 4; PUFA, polyunsaturated fatty acids; PUFA-CoA, polyunsaturated fatty acyl CoA; PL-PUFA, phospholipid-bound polyunsaturated fatty acids; PLOOH, phospholipid hydroperoxides; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; ALOXs, arachidonic acid lipoxygenases; Gly, glycine; Cys₂, cysteine residues; Cys, cysteine; GSS, glutathione synthetase; γGSC, γ-glutamylcysteinyl synthetase; γGlu-Cys, γglutamyl-cysteine; GSH, glutathione; GPX4, glutathione peroxidase 4; GSSG, glutathione oxidized; GSR, glutathione-disulfide reductase; NADPH, nicotinamide adenine dinucleotide phosphate; NADP⁺, the oxidized form of NADPH; GGT, Glutamyl transpeptidase.

Figure 2

Mechanism of ferritinophagy. NCOA4 mediated ferritinophagy transports intracellular ferritin to autophagy lysosome for degradation and release free iron. By overloading intracellular iron, ROS production in the labile iron pool increases, so as to increase the sensitivity of cells to ferroptosis. NCOA4, nuclear receptor co-activator 4; ROS, reactive oxygen species.

Figure 3

Mechanism of ferroptosis and ferritinophagy involved in diabetes complications. HIF-1α, hypoxia-inducible factor-1α; HO-1, heme oxygenase-1; NRF2, nuclear factor E2-related factor 2; FTH-1,ferritin heavy chain-1; TFR-1, transferrin receptor-1; HSF1，heat shock factor 1; TRIM46, tripartite motif-containing 46; GPX4, glutathione peroxidase 4; ACSL4, acyl-CoA synthetase long-chain family member 4; DN, diabetic nephropathy; DR, diabetic retinopathy; DCM, diabetic cardiomyopathy.