G3BP2 facilitates abnormal activation of fibroblast-like synoviocytes through p53 signaling pathway in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and joint destruction. While GTPase-activating protein SH3 domain-binding protein 2 (G3BP2) plays important roles in tumors and other diseases, its function in RA remains unclear. Our study demonstrated significant upregulation of G3BP2 in fibroblast-like synoviocytes (FLSs) from RA patients, which was further enhanced by TNF-α stimulation. Both G3BP2 knockdown using siRNA and pharmacological inhibition with compound C108 effectively suppressed TNF-α-induced RA-FLS migration, invasion, and reduced the secretion of IL-1β and VEGF-A as well as the expression of N-cadherin. RNA sequencing analysis revealed that compound C108 modulates the p53 signaling pathway. Mechanistically, both G3BP2 silencing and C108 treatment enhanced p53 expression by reducing its ubiquitination, thereby activating p53 signaling. Importantly, the p53 inhibitor PFT-α reversed the inhibitory effects of C108 on TNF-α-induced RA-FLS migration, invasion, and cytokine expression. In adjuvant-induced arthritis (AA) rat models, intra-articular injection of compound C108 (4 and 8 μM) significantly alleviated arthritis symptoms, reduced synovial hyperplasia, downregulated G3BP2, N-cadherin, IL-1β, and MMP3 expression, while promoting p53 expression in FLSs of AA rats. Our findings demonstrate that G3BP2 promotes abnormal activation of RA-FLSs by suppressing p53 signaling, suggesting G3BP2 as a promising therapeutic target for RA treatment.