USP5 promotes glycolysis of fibroblast-like synoviocytes by stabilizing the METTL14/m6A/GLUT1 axis in rheumatoid arthritis.

Fibroblast-like synoviocytes (FLSs) contribute to the advancement of rheumatoid arthritis (RA) through enhanced metabolic reprogramming. This research focused on exploring the role and underlying mechanism of ubiquitin-specific protease 5 (USP5) in modulating the glycolysis and activation of RA-FLSs. Here, we identified that knockdown of USP5 in RA rats reduced synovial inflammation and glycolytic activity, as evidenced by decreased serum lactate levels and GLUT1 expression. In RA-FLSs, USP5 knockdown or treatment with 2-DG reduced cell proliferation, migration, invasion, cytokine production, and glycolysis, while increased apoptosis. Mechanistically, USP5 stabilized METTL14 by inhibiting its ubiquitination, while METTL14 enhanced the m6A modification of GLUT1 mRNA, thereby increasing its expression. Furthermore, overexpression of METTL14 partially reversed the effects of USP5 knockdown on glycolysis and inflammatory activation in RA-FLSs. Additionally, knockdown of METTL14 inhibited RA-FLS glycolysis and inflammatory activation by downregulating GLUT1. Collectively, USP5 stabilized METTL14-mediated m6A modification of GLUT1 by inhibiting the ubiquitination of METTL14, thereby enhancing glycolysis and inflammatory activation in RA-FLSs. These results suggest that the USP5/METTL14/GLUT1 axis could be a potential therapeutic target for RA.