Ferroptosis: A potential therapeutic target in autoimmune disease (Review)

Abstract

Ferroptosis is a distinct type of regulated cell death characterized by iron overload and lipid peroxidation. Ferroptosis is regulated by numerous factors and controlled by several mechanisms. This cell death type has a relationship with the immune system, which may be regulated by damage-associated molecular patterns. Ferroptosis participates in the progression of autoimmune diseases, including autoimmune hepatitis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, Parkinson's Disease, psoriasis and insulin-dependent diabetes mellitus. The present review summarizes the role of ferroptosis in autoimmune disorders and discusses ferroptosis as a potential therapeutic target for autoimmune disease.

Keywords: autoimmune disease; ferroptosis; immune system; therapeutic target.

Figure 1

Signaling pathway of ferroptosis. Ferric iron is transferred into cells by TfR1, then converted to ferrous iron and released to the cytoplasm by STEAP3 and DMT1. Elevated labile iron pool catalyzes formation of phospholipid hydroperoxides via Fenton reaction. Free cytosolic PUFAs are converted to PUFA-PLs with catalyzation by ACSL4 and LPCAT3, then PUFA-PLs are oxidized by lipoxygenase 12/15, contributing to the accumulation of phospholipid hydroperoxides. Mitochondrial dysfunction results in increased ROS production, which may also contribute to lipid peroxidation. Cystine uptake through system xc- is used for synthesis of GSH. Moreover, FSP1/CoQ10 and GCH1/BH4/BH2 are two parallel GPX4-independent pathways in suppression of ferroptosis. TfR1, transferrin receptor 1; DMT1, divalent metal transporter 1; NCOA4, nuclear receptor coactivator 4; PUFA, polyunsaturated fatty acid; ACSL4, acyl-CoA synthetase long-chain family member 4; LPCAT3, lysophosphatidylcholine acyltransferase 3; GSH, glutathione; FSP1, ferroptosis suppressor protein 1; GCH-1, guanosine triphosphate cyclohydrolase 1; BH4, tetrahydrobiopterin; BH2, dihydrobiopterin; PL, phospholipid; GSR, glutathione disulfide reductase; GSSG, glutathione oxidized; ROS, reactive oxygen species; GPX4, GSH peroxidase 4; CoQ10H2, reduced coenzyme Q10; ETC, electron transport chain.