The Nrf2‐GPX4 Pathway Provides Protection Against Rheumatoid Arthritis via Inhibition of Macrophage Ferroptosis‐Mediated Inflammation and Synovial Fibroblast Proliferation

Abnormal activation and proliferation of rheumatoid arthritis synovial fibroblasts (RASFs) play an important role in rheumatoid arthritis (RA), the mechanism of which remains elusive. The purpose of our study is to comprehensively explore the mechanism of the Nrf2-GPX4 pathway-mediated abnormal RASF activation in RA. Here, we found that Nrf2 and GPX4 protein expression levels were downregulated in the synovial tissues of complete Freund's adjuvant (CFA)-induced adjuvant-induced arthritis (AIA) rats compared with those in control rats. However, Nrf2-GPX4 activation by the Nrf2 activator CDDO-EA could abrogate the CFA-induced macrophage ferroptosis and inflammatory response, as suggested by decreased levels of 5-HT, TNF-α, IL-6, MDA, Fe²⁺, and lipid peroxidation, yet increased levels of SOD and GSH. As such, Nrf2-GPX4 relieved CFA-induced arthritis in rats. We further found that Nrf2-GPX4 activation arrested macrophage ferroptosis and M1 polarization, and restrained RASF proliferation in vitro. More strikingly, these effects of Nrf2-GPX4 could be partially abolished by the ferroptosis inducer RSL-3. In conclusion, our study provides the first evidence that activated Nrf2-GPX4 can retard RA by suppressing macrophage ferroptosis, M1 polarization, and RASF proliferation. These results provide a new perspective for understanding RA pathogenesis and finding new therapeutic targets.