Ferroptosis as an emerging target in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology. Due to the rise in the incidence rate of RA and the limitations of existing therapies, the search for new treatment strategies for RA has become a global focus. Ferroptosis is a novel programmed cell death characterized by iron-dependent lipid peroxidation, with distinct differences from apoptosis, autophagy, and necrosis. Under the conditions of iron accumulation and the glutathione peroxidase 4 (GPX4) activity loss, the lethal accumulation of lipid peroxide is the direct cause of ferroptosis. Ferroptosis mediates inflammation, oxidative stress, and lipid oxidative damage processes, and also participates in the occurrence and pathological progression of inflammatory joint diseases including RA. This review provides insight into the role and mechanism of ferroptosis in RA and discusses the potential and challenges of ferroptosis as a new therapeutic strategy for RA, with an effort to provide new targets for RA prevention and treatment.

Keywords: emerging target; ferroptosis; iron metabolism; lipid peroxidation; rheumatoid arthritis.

Figure 1

Mechanisms of iron metabolism: FPN1, iron transporter protein; TfR1, transferrin receptor 1; FTL, ferritin light chain; FTH, ferritin heavy chain; NCOA4, nuclear receptor coactivator 4; LIP, labile iron pool; ROS, reactive oxygen species; STEAP3, six-transmembrane epithelial antigen of the prostate 3; DMT1, divalent metal transporter protein 1.

Figure 2

Ferroptosis mechanism: Ferroptosis is mainly caused by iron-dependent lipid peroxidation. It is mainly divided into ferroptosis promotion pathway (blue) and ferroptosis inhibition pathway (purple) (1). Iron metabolic pathway (2). Cystine/glutamate (also known as Xc-system)-GSH-GPX4 pathway: Cystine is imported into cells via the Xc-system, where it is oxidized to cysteine (Cys), followed by the synthesis of glutathione (GSH) in the presence of glutamate-cysteine ligase (GCL) and glutathione synthase (GSS). GSH is a potent reducing agent. GPX4 inhibits ferroptosis by using GSH as a reducing cofactor to reduce lipid hydroperoxides to lipid alcohols (3). Mevalonate pathway: Acetyl coenzyme A is first converted to HMG-CoA, which is then reduced to mevalonate by HMGCR, and mevalonate is converted to IPP. Finally, selenocysteine residues are added to the catalytic center of GPX4 to activate GPX4. At the same time, IPP can also produce coenzyme Q10 and then enter the FSP1 pathway (4). Lipid metabolic pathway: PUFAs are metabolized by ACSL4 and LPCAT3 and then oxidized by lipoxygenase HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; IPP, isopentenyl pyrophosphate; GPX4, glutathione peroxidase 4; SLC1A5, solute carrier family 1 member 5; GLS, glutaminase; SLC3A2, solute carrier family 3 member 2. SLC7A11, solute carrier family 7 member 11; GSH, glutathione; Xc- system: glutamate reverse transporter protein, GPX4: glutathione peroxidase 4.

Figure 3

The key role of ferroptosis in inflammatory damage, mitochondria, blood vessels. bone, synovial membrane, and articular cartilage.

Figure 4

Mechanism of ferroptosis in RA synovium Lipid peroxides as well as iron deposition can be seen in RA synovium. In addition, proinflammatory factors secreted by immune cells and FLS in RA synovium promote oxidative stress, which in turn further exacerbates the inflammatory response, and through this vicious circle, ferroptosis and synovial inflammation are promoted, FLS, fibroblast-like synoviocyte; IL-6, interleukin 6; RNS, reactive nitrogen species; ROS, reactive oxygen species; TNF, tumor necrosis factor; RANKL, Receptor Activator for Nuclear Factor-kB Ligand; MMPs, matrix metalloproteinases.