The emerging role of ferroptosis in intestinal disease

Abstract

Ferroptosis is a newly recognised type of regulated cell death (RCD) characterised by iron-dependent accumulation of lipid peroxidation. It is significantly distinct from other RCDs at the morphological, biochemical, and genetic levels. Recent reports have implicated ferroptosis in multiple diseases, including neurological disorders, kidney injury, liver diseases, and cancer. Ferroptotic cell death has also been associated with dysfunction of the intestinal epithelium, which contributes to several intestinal diseases. Research on ferroptosis may provide a new understanding of intestinal disease pathogenesis that benefits clinical treatment. In this review, we provide an overview of ferroptosis and its underlying mechanisms, then describe its emerging role in intestinal diseases, including intestinal ischaemia/reperfusion (I/R) injury, inflammatory bowel disease (IBD), and colorectal cancer (CRC).

Fig. 1. Mechanisms of ferroptosis.

Ferroptosis is characterised by iron accumulation, excessive ROS production and overwhelming lipid peroxidation. Three main metabolic pathways, amino-acid/GSH, lipid, and iron pathways, participate in the initiation and execution of ferroptosis. Moreover, there are additional signalling pathways and regulators controlling ferroptosis sensitivity. This illustration shows the process of ferroptosis, summarising the key molecules and targets that regulate iron and lipid peroxidation. ACSL4 acyl-CoA synthetase long-chain family member 4, BSO buthionine sulphoximine, CISD1 CDGSH iron sulphur domain 1, DMT1 divalent metal transporter 1, FSP1 ferroptosis suppressor protein 1, FPN1 ferroportin 1, GPX4 glutathione peroxidase 4, GSH glutathione, GSSG oxidized glutathione, GSS glutathione synthetase, GCL glutamate-cysteine ligase, HO-1 haem oxygenase 1, HSPB1 heat shock protein beta-1, IREB2 iron response element-binding protein 2, LOX lipoxygenase, LPCAT3 lysophosphatidylcholine acyltransferase 3, NCOA4 nuclear receptor coactivator 4, NRF2 nuclear factor E2-related factor 2, PUFA polyunsaturated fatty acid, PE phosphatidylethanolamine, ROS reactive oxygen species, RSL3 Ras-selective lethal 3, STEAP3 six-transmembrane epithelial antigen of prostate 3 metalloreductase, SLC7A11 solute carrier family 7 member 11, SAS sulphasalazine, SRF sorafenib, TF transferrin, TFR1 transferrin receptor 1, VDAC2/3 voltage dependent-anion channel 2/3.

Fig. 2. Dual regulatory roles for ferroptosis in intestinal diseases.

Ferroptosis can be a positive and negative regulator of intestinal diseases according to cell type and disease context. The induction of ferroptosis by multiple compounds can inhibit cancer growth; however, inhibiting ferroptosis has an anti-inflammatory effect and can attenuate intestinal injury in IBD and I/R injury. This schematic diagram shows ferroptosis regulators and pathways. ACADSB acyl-Coenzyme A dehydrogenase short/branched chain, ACSL4 acyl-CoA synthetase long-chain family member 4, ANO6 anoctamin 6, CRC colorectal cancer, CXCL1 chemokine (C-X-C motif) ligand 1, DFO deferoxamine, DPP4 dipeptidyl-peptidase-4, ER endoplasmic reticulum, Fer-1 ferrostatin-1, FTL ferritin light chain, FTH1 ferritin heavy chain 1, FeOOH NS iron oxide-hydroxide nanospindle, GPX4 glutathione peroxidase 4, GSH glutathione, HO-1 haem oxygenase 1, IMCA 2-Imino-6-methoxy-2H-chromene-3-carbothioamide, I/R ischaemia/reperfusion, IBD inflammatory bowel disease, IL-6 interleukin 6, KD knockdown, Lip-1 liproxstatin-1, NOX1 NADPH oxidase 1, NRF2 nuclear factor E2-related factor 2, PUFA polyunsaturated fatty acid, PE phosphatidylethanolamine, ROS reactive oxygen species, RSL3 Ras-selective lethal small molecule 3, SLC7A11 solute carrier family 7 member 11, TFR1 transferrin receptor 1.

Fig. 3. p53-mediated ferroptosis.

p53 plays a dual role in the regulation of ferroptosis through transcriptional or posttranslational mechanisms in different contexts. On one hand, p53 induces ferroptosis through inhibition of SLC7A11 or upregulation of GSL2 and SAT1–ALOX pathway. On the other hand, p53 also inhibits ferroptosis through inhibition of DPP4 activity or by the transcriptional activation of CDKN1A/p21. ALOX arachidonate lipoxygenase, CDKN1A cyclin-dependent kinase inhibitor 1 A, DPP4 dipeptidyl-peptidase-4, GLS2 glutaminase 2, GSH glutathione, NOX1 NADPH oxidase 1, ROS reactive oxygen species, SAT1 spermidine/spermine N1-acetyltransferase 1, SLC7A11 solute carrier family 7 member 11.