Role of ferroptosis in the pathogenesis and as a therapeutic target of inflammatory bowel disease (Review)

Abstract

Ferroptosis, a novel form of regulated cell death, is characterized by the accumulation of labile iron and lipid peroxidation, and the excessive production of reactive oxygen species (ROS). Although ferroptosis lies at the center of crucial biological activities involving O2, iron and polyunsaturated fatty acids (PUFAs), which are essential for cell proliferation and growth, the interaction between these molecules could also mediate the accumulation of toxic levels of ROS and lipid peroxides, which can then cause damage to cellular membranes and ultimately result in cell death. Recent reports have indicated that ferroptosis participates in the development and progression of inflammatory bowel disease (IBD), offering a new exploratory field which may aid in the more in‑depth understanding of the pathogenesis and therapeutic targets of IBD. Of note, the mitigation of the characteristic features of ferroptosis, such as depleted glutathione (GSH) levels, inactivated glutathione peroxidase 4 (GPX4), elevated levels of lipid peroxidation and iron overload significantly relieve IBD. This has attracted the attention of researches aiming to examine therapeutic agents that inhibit ferroptosis in IBD, including radical‑trapping antioxidants, enzyme inhibitors, iron chelators, protein degradation inhibitors, stem cell‑derived exosomes and oral N‑acetylcysteine or glutathione. The present review summarizes and discusses the current data that implicate ferroptosis in the pathogenesis of IBD and its inhibition as a novel alternate therapeutic target for IBD. The mechanisms and key mediators of ferroptosis, including GSH/GPX4, PUFAs, iron and organic peroxides are also discussed. Although the field is relatively new, the therapeutic regulation of ferroptosis has exhibited promising outcomes as a novel treatment avenue for IBD.

Keywords: ferroptosis; glutathione peroxidase 4; inflammatory bowel disease; intestinal disease; iron overload; lipid peroxidation.

Figure 1

Mechanisms of ferroptosis. System X_C⁻ and glutamine transporter allow the influx of cystine and glutamine, respectively, which are converted into cysteine and glutamate. Cysteine combines with glutamate to form glutamylcysteine by γ-GCS, followed by conversion to GSH under the action of GS. GSH and GPX4 serve as scavengers of ROS to prevent oxidative stress and lipid peroxidation. However, the inhibition of system Xc- by agents, such as erastin and FIN56 depletes GSH, leading to increased ROS and lipid peroxidation. Moreover, while RSL3, FINO2 and FIN56 can directly inhibit GPX4 to promote lipid peroxidation, p53 and PEBP1 enhance the activity of LOX to promote lipid peroxidation, resulting in ferroptosis. In addition, POR, LOX and the Fenton reaction chain promote the conversion of PE-PUFA to PE-PUFA-OOH, leading to ferroptosis. GSH, glutathione; GS, GSH synthetase; γ-GCS, γ-glutamylcysteine synthetase; GPX4, glutathione peroxidase 4; PUFA, polyunsaturated fatty acid; GOT1, glutamate oxaloacetate transaminase 1; GSSG, oxidized glutathione; ROS, reactive oxygen species; LOX, lipoxygenase; POR, cytochrome P450 oxidoreductase, ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; PEBP1, phosphatidylethanolamine-binding protein-1; PL, phospholipid; PLOOH, phospholipid hydroperoxides; PE, phosphatidylethanolamine; RSL3, RAS-selective lethal 3.

Figure 2

Role of key negative mediators of ferroptosis. (A) PUFA serves as one of the drivers of ferroptosis. The increased accumulation of cellular irons triggers the oxidation of PUFA to PUFA-OOH, which is promoted by PHKG2, leading to ferroptosis. ELOVLS and FADS1 enhance cellular sensitivity to ferroptosis, while D-PUFA inhibits the oxidation of PUFAs. (B) Iron, both Fe²⁺ and Fe³⁺, induces lipid peroxidation through the Fenton chain reaction by interacting with PL-OOH to produce PLOO· and PLO·, respectively, and through the enzymatic route, POR and LOX, to produce cellular ROS that drives ferroptosis. (C) Organic peroxides contribute to ferroptosis by ROS production. FINO2, a typical organic peroxide drives ferroptosis by either inhibiting GPX4 or oxidizing iron to release ROS, causing lipid peroxidation and subsequently, ferroptosis. PUFA, polyunsaturated fatty acid; PUFA-OOH, polyunsaturated fatty acid containing-phospholipid hydroperoxides; PHKG2, phosphorylase kinase G2; PLOOH, phospholipid hydroperoxides; LOX, lipoxygenase; POR, cytochrome P450 oxidoreductase; ROS, reactive oxygen species; GPX4, glutathione peroxidase 4.

Figure 3

Role of ferroptosis in the pathology of inflammatory bowel disease. In the gut, lipid peroxidation, which is driven by depleted GSH, inactive GPX4 and elevated iron levels, leads to increased ferroptosis that consequently promotes epithelial cell erosion. Other factors, such as ER stress and dysregulated genes contribute to chronic inflammation, ROS generation and ferroptosis. GSH, glutathione; GPX4, glutathione peroxidase 4; ROS, reactive oxygen species; ER, endoplasmic reticulum, MDA, malondialdehyde; COX2, cyclooxygenase 2; eIF2α, eukaryotic translation initiation factor 2α; ORMDL2, ORMDL sphingolipid biosynthesis regulator 2; AGR2, anterior gradient protein 2 homolog; XBP1, X-box binding protein 1; SLC38A1, solute carrier family 38, member 1; G6PD, glucose-6-phosphate dehydrogenase; GPX4, glutathione peroxidase 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; NCOA4, nuclear receptor coactivator 4; ACSL4, acyl-CoA synthetase long-chain family member 4; ACSF2, acyl-CoA synthetase family member 2.

Figure 4

Therapies that target ferroptosis in IBD. As presented in the present review, seven categories of therapies, among others, have been explored for the inhibition of ferroptosis in various IBD models. The majority of these therapies have shown promising effects that lead to the mitigation of IBD. IBD, inflammatory bowel disease.