Targeting Ferroptosis as a Promising Therapeutic Strategy for Ischemia-Reperfusion Injury

Abstract

Ischemia-reperfusion (I/R) injury is a major challenge in perioperative medicine that contributes to pathological damage in various conditions, including ischemic stroke, myocardial infarction, acute lung injury, liver transplantation, acute kidney injury and hemorrhagic shock. I/R damage is often irreversible, and current treatments for I/R injury are limited. Ferroptosis, a type of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides, has been implicated in multiple diseases, including I/R injury. Emerging evidence suggests that ferroptosis can serve as a therapeutic target to alleviate I/R injury, and pharmacological strategies targeting ferroptosis have been developed in I/R models. Here, we systematically summarize recent advances in research on ferroptosis in I/R injury and provide a comprehensive analysis of ferroptosis-regulated genes investigated in the context of I/R, as well as the therapeutic applications of ferroptosis regulators, to provide insights into developing therapeutic strategies for this devastating disease.

Keywords: antioxidant; ferroptosis; iron; ischemia-reperfusion injury; therapeutic strategies.

Figure 1

Overview of the regulatory mechanism of ferroptosis in ischemia-reperfusion. I/R, ischemia-reperfusion; Glu, glutamate; Cys, cystine; SLC3A2, solute carrier family 3 member 2; SLC7A11, solute carrier family 7 member 11; p21, cyclin dependent kinase inhibitor 1A; p53, protein 53; GSH, glutathione; GSSG, glutathione oxidized; Se, selenium; GPX4, glutathione peroxidase 4; SAT1, spermidine/spermine N1-acetyltransferase 1; ALOX-15, arachidonate lipoxygenase 15; NADPH, nicotinamide adenine dinucleotide phosphate; CoQ10, coenzyme Q10; FSP1, ferroptosis suppressor protein 1; HSPB1, heat shock factor-binding protein 1; TfR1, transferrin receptor 1; FPN, ferroportin; STEAP3, six transmembrane epithelial antigen of the prostate 3; DMT1, divalent metal-ion transporter-1; IREB2, iron response element-binding protein 2; NCOA4, nuclear receptor coactivator 4; LOXs, lipoxygenases; PUFA, polyunsaturated fatty acids; PUFA-PE, polyunsaturated phosphatidylethanolamines; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; HO-1, heme oxygenase 1; Nrf2, nuclear factor erythroid 2-related factor 2; Keap1, kelch-like ECH-associated protein 1; p62, sequestosome 1.

Figure 2

Therapeutic strategies targeting ferroptosis in ischemia-reperfusion injury. Regulatory genes and pharmacological therapies of ferroptosis investigated in I/R injury are summarized in the figure. Green capsules represent well-recognized ferroptosis inhibitors, red capsules represent agents studied in cerebral I/R injury, purple for myocardial, yellow for lung, blue for renal and gray for intestinal. I/R, ischemia-reperfusion; GPX4, glutathione peroxidase 4; ACSL4, acyl-CoA synthetase long-chain family member 4; NCOA4, nuclear receptor coactivator 4; SLC7A11, solute carrier family 7 member 11; Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase 1; MAO-B, monoamine oxidase b; IREB2, iron response element-binding protein 2; TfR1, transferrin receptor 1; AMPKα2, adenosine 5′-monophosphate-activated protein kinase α2; p53, protein 53; FPN, ferroportin; USP7, ubiquitin-specific peptidase 7; USP14, ubiquitin-specific peptidase 14; USP19, ubiquitin-specific peptidase 19; USP22, ubiquitin-specific peptidase 22; TRF, transferrin; Gln, glutamine; MiR, microRNA; OxPCs, oxidized phosphatidylcholines; LncRNA, long non-coding RNA; ELAVL1, embryonic lethal-abnormal vision like protein 1; DNMT-1, DNA (cytosine-5)-methyltransferase 1; Nrf2, nuclear factor erythroid 2-related factor 2; TERT, telomerase reverse transcriptase; STAT3, signal transducer and activator of transcription 3; Sp1, special protein 1; TRPV1, transient receptor potential cation channel subfamily V member 1; LSD1, lysine- specific demethylase 1; Panx1, pannexin 1; CIRBP, cold-inducible RNA-binding protein; IDO, indoleamine 2,3-dioxy-genase 1; ALR, augmenter of liver regeneration; HUWE1, HECT domain-containing ubiquitin E3 ligase; SAT1, spermidine/spermine N1-acetyltransferase 1; PVT1, plasmacytoma variant 1; UBIAD1, UbiA prenyltransferase domain containing 1; PGE2, prostaglandin E2; Fer-1, ferrostatin-1; Lip-1, liproxstatin-1; DFO, deferoxamine; DXZ, dexrazoxane; α-Toc, α-tocopherol; GAA, gossypol acetic acid; C3G, cyanidin-3-glucoside; XN, xanthohumol; HC, histochrome; PDA NPs, polydopamine nanoparticles; APG, apigenin-7-O-β-D-(-6′′-p-coumaroyl)-glucopyranoside; CAR, carvacrol; Se, selenium; Res, resveratrol; CAT, capsiate; CY, carthamin yellow; ROSI, rosiglitazone; KF, kaempferol; DEX, dexmedetomidine; QCT, quercetin; FA, ferulic acid; iASPP, inhibitor of apoptosis-stimulating protein of p53; Eto, etomidate; NAR, naringenin; Bri, britanin; PA, pachymic acid; IA, isoliquiritin apioside.