Ferroptosis in inflammatory arthritis: A promising future

Abstract

Ferroptosis is a kind of regulatory cell death (RCD) caused by iron accumulation and lipid peroxidation, which is characterized by mitochondrial morphological changes and has a complex regulatory network. Ferroptosis has been gradually emphasized in the pathogenesis of inflammatory arthritis. In this review, we summarized the relevant research on ferroptosis in various inflammatory arthritis including rheumatoid arthritis (RA), osteoarthritis, gout arthritis, and ankylosing spondylitis, and focused on the relationship between RA and ferroptosis. In patients with RA and animal models of RA, there was evidence of iron overload and lipid peroxidation, as well as mitochondrial dysfunction that may be associated with ferroptosis. Ferroptosis inducers have shown good application prospects in tumor therapy, and some anti-rheumatic drugs such as methotrexate and sulfasalazine have been shown to have ferroptosis modulating effects. These phenomena suggest that the role of ferroptosis in the pathogenesis of inflammatory arthritis will be worth further study. The development of therapeutic strategies targeting ferroptosis for patients with inflammatory arthritis may be a promising future.

Keywords: cell death; ferroptosis; inflammatory arthritis; iron accumulation; lipid peroxidation.

Figure 1

Diagram about mechanism of ferroptosis. ACSL4, acyl-CoA synthetase long-chain family member 4; CISD1, CDGSH iron sulfur domain 1; DAMPs, damage-associated molecular patterns; DMT1, divalent metal transporter 1; F2-I, isoprostane; FPN, ferroportin; FSP1, ferropsis -suppressor-protein 1; FTH, ferritin heavy chain; FTL, ferritin light chain; FtMt, mitochondrial ferritin; Glu, glutamate; GSH, glutathione; GSSG, oxidized glutathione; GPX4, glutathione peroxidase 4; 4-HNE, 4-hydroxynonenal; HSPA5, heat shock protein family A member 5; HSPB1, heat shock protein beta-1; LOX, lipoxygenase; LPCAT3, lysophosphatidylcholine acyltransferase 3; MAA, malondialdehyde-acetaldehyde; MDA, malonaldehyde; mitoROS, mitochondrial reactive oxygen species; NCOA4, nuclear receptor coactivator 4; NOX2, nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase2; Nrf2, nuclear factor erythroid 2-related factor 2; OXPHOS, oxidative phosphorylation; PL, phospholipids; POR, cytochrome P450 oxidoreductase; PUFAs, polyunsaturated fatty acids; ROS, reactive oxygen species; STEAP3, six-transmembrane epithelial antigen of the prostate 3; TfR1, transferrin receptor 1; VDAC, voltage-dependent anion channels; ZIP8/14, Zinc-Iron regulatory protein family 8/14. There are four main sections in the figure showing the mechanism of ferroptosis. The green squares mainly show the metabolic process of iron after entering the cell, including reduction, storage and release, and then active iron becomes an important factor in promoting lipid peroxidation. The pink squares show the process of lipid peroxidation, including the binding of PUFAs and PL, followed by the peroxidation of this complex by ROS and the release of downstream products. The yellow squares show the role of the cellular antioxidant system. GPX4 is the only enzyme that can reduce lipid peroxides, whose inactivation is thought to be the central part of ferroptosis. The content in the dark blue background shows the major changes in mitochondria during ferroptosis, including morphological changes and biochemical reactions. These processes can be modulated by several regulatory factors. The result of ferroptosis is cell rupture and the release of DAMPs.

Figure 2

Diagram about the role of ferroptosis in RA. DMT1, divalent metal transporter 1; F2-I, isoprostane; FLS, fibroblast-like synoviocyte; FTH1, ferritin heavy chain 1; FTL, ferritin light chain; GSH, glutathione; GPX4, glutathione peroxidase 4; HSPA5, heat shock protein family A member 5; 4-HNE, 4-hydroxynonenal; IFN-γ, interferon-γ; IL-1β, interleukin-1β; IL-6, interleukin-6; MDA; malonaldehyde; NCOA4, nuclear receptor coactivator 4; Nrf2, nuclear factor erythroid 2-related factor 2; RBC, red blood cell; sTfR, soluble transferrin receptor; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor. Lipid peroxidation were observed in the blood, synovial tissue and synovial fluid of RA patients, as well as iron deposition in the synovium. There was evidence of ferroptosis in RA-FLSs and macrophages, but it has not been determined whether ferroptosis is hyperactive or inhibited. TNF could reduce the ferroptosis sensitivity of FLSs through TNFR, while other cytokines, including IL-1, IL-6, TGF-β and IFN-γ, could promote ferroptosis in FLSs.