Study of the mechanism of fibroblast-like synoviocytes-derived exosomes inducing macrophages M1 polarization and CD8+T cells immune regulation ferroptosis and autophagy in rheumatoid arthritis.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects the joints. The pathogenesis of RA is complex, involving membrane lipid antioxidant systems, oxidative stress, and lipid peroxidation. In this study, it was found that cysteine dioxygenase 1 (CDO1) is significantly upregulated in RA fibroblast-like synoviocytes (RA-FLS) and that exosomes derived from these RA-FLS deliver CDO1 to promote M1 polarization of macrophages, thus facilitating RA progression. In the immune microenvironment, CD8⁺T cells play a role in immune regulation by producing cytokines such as interferon gamma (IFNγ) in various diseases. The results of this study suggested that in RA-FLS, CD8⁺T cells deliver IFNγ, which not only inhibits the viability of RA-FLS but also affects glutathione (GSH) through CDO1, regulating the GPX4 antioxidant signaling pathway to promote ferroptosis and autophagy in cells. It was also discovered that IFNγ enhances the expression of TRI69, ubiquitinates and degrades FSP1, thereby forming a cooperative regulation process of GPX4 and FSP1 in ferroptosis. These findings provide a new direction for the treatment of RA.