Ferroptosis in Rheumatoid Arthritis: A Potential Therapeutic Strategy

Abstract

Ferroptosis is one of the newly discovered forms of cell-regulated death characterized by iron-dependent lipid peroxidation. Extensive research has focused on the roles of ferroptosis in tumors, blood diseases, and neurological diseases. Some recent findings have indicated that ferroptosis may also be related to the occurrence and development of inflammatory arthritis. Ferroptosis may be a potential therapeutic target, and few studies in vitro and animal models have shown implications in the pathogenesis of inflammatory arthritis. This mini review discussed the common features between ferroptosis and the pathogenesis of rheumatoid arthritis (RA), and evaluated therapeutic applications of ferroptosis regulators in preclinical and clinical research. Some critical issues worth paying attention to were also raised to guide future research efforts.

Keywords: ferroptosis; lipid peroxidation; reactive oxygen species; rheumatoid arthritis; therapeutic strategy.

Figure 1

After the transferrin binds to the transferrin receptor on the plasma membrane, the plasma membrane forms a vesicle that takes Fe³⁺ carrying transferrin into the cell. Then, the low pH in the vesicle promotes the separation of Fe³⁺ from the transferrin and the shedding of Fe³⁺. It is reduced to Fe²⁺ and free in the cytoplasm, or is combined with ferritin to form an iron pool. The ferritin in the iron pool can be encapsulated by autophagy lysosomes under the mediation of NCOA4, and then degraded and release a large amount of Fe²⁺. Fe²⁺ and H₂O₂ generate PLOOH through the fenton reaction, which promotes ferroptosis by promoting further lipid peroxidation and self-peroxidation. In the GSH/GPX4 pathway, with the help of GSH, GPX4 down-regulates ROS and inhibits ferroptosis. This can be suppressed by RSL3. System Xc- (cystine/glutamate antiporter) promotes synthesis of glutathione, which can be offset by erastin, sulfasalazine and sorafenib. In the FSP1 protection pathway, FSP1 can catalyze the reduction of CoQ10 to panthenol and consume NAD(P)H to inhibit ROS. In the GCH1 protection pathway, GCH1 acts as a rate-limiting enzyme to manage the biosynthesis of BH4 and reduce ferroptosis.

Figure 2

ROS is a critical element of the ROS/TNF-α feedback loop. The production of TNF-α depends on the activation of ROS-stimulated NF-κB signaling, which activates the p38/JNK signaling pathway to accelerate the progression of RA inflammation. High levels of iron ions can catalyze the production of ROS. Excessive ROS will aggravate the proliferation of synovial fibroblasts; induce osteoclast differentiation and inhibit osteoblast proliferation; activate metalloproteinases, as well as lead to cartilage destruction and bone erosion. Excessive ROS will also promote lipid peroxidation, leading to cell ferroptosis. Moreover, the ferroptosis inducer (erastin) can promote the expression of matrix metalloproteinase 13 and promote cartilage destruction, while the ferroptosis inhibitor ferrostatin-1 can reduce cartilage degradation.