METTL3 increases ferroptosis resistance to facilitate the tumor-like features of rheumatoid arthritis synovial fibroblasts through enhancing SLC7A11 mRNA stability in an m6A-IGF2BP2-dependent manner

Activated rheumatoid arthritis synovial fibroblasts (RASFs) exhibit tumor-like properties, which play a significant role in joint degradation in RA. The prevalence of N6-methyladenosine (m6A) as a modification in mRNA is involved in diverse biological processes; however, its specific implications in the pathogenesis of RA have yet to be fully elucidated. This study seeks to explore the impact and underlying mechanisms of m6A methylation on the proliferation, migration, and invasion of RASFs. Our study revealed an upregulation of METTL3 expression in synovium and SFs from patients with RA. Moreover, knockdown of METTL3 resulted in decreased proliferation, migration, and invasion of RASFs. Mechanistically, METTL3 mediated m6A modification in the SLC7A11 mRNA, enhancing its stability through interaction with insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2). Furthermore, knockdown of METTL3 accelerated erastin-induced ferroptosis and further inhibited tumor-like characteristics in RASFs. Additionally, intra-articular injection of lentivirus-shMETTL3 showed promising results in reducing arthritis severity and inhibiting aggressive behaviors of SFs in a CIA mouse model. Our findings indicate that the METTL3-mediated m6A modification plays a critical role in the pathogenesis of synovial hyperplasia and invasion in RA. Therapeutic interventions aimed at targeting METTL3 may offer a novel approach for the treatment of RA.