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The following is a summary of “METTL3-mediated methylation of RAC2 contributes to cell motility, oxidative stress and inflammation in TNF‐α-stimulated rheumatoid arthritis fibroblast-like synovial cells,” published in the February 2025 issue of the Journal of Orthopaedic Surgery and Research by Ren et al.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by persistent joint inflammation and progressive cartilage and bone destruction, significantly impacting patients’ quality of life. Emerging evidence suggests that RNA methylation, particularly N6-methyladenosine (m6A) modification, plays a crucial role in RA pathogenesis. This study aimed to elucidate the regulatory function of methyltransferase-like 3 (METTL3) in RA, specifically its role in modulating the expression of ras-related C3 botulinum toxin substrate 2 (RAC2) through m6A methylation. To establish an in vitro RA model, MH7A synovial fibroblast cells were stimulated with tumor necrosis factor-alpha (TNF‐α). Quantitative real-time PCR and western blot analysis were performed to assess gene and protein expression levels. 

Cell proliferation, apoptosis, migration, and invasion were evaluated using CCK-8 assay, flow cytometry, wound healing assay, and transwell assay, respectively. Oxidative stress markers were quantified to assess cellular redox balance, while inflammatory cytokine levels were determined via enzyme-linked immunosorbent assay (ELISA). RNA immunoprecipitation (RIP) and methylated RNA immunoprecipitation (MeRIP) assays were conducted to investigate the interaction between METTL3 and RAC2. The results demonstrated that RAC2 was significantly upregulated in RA synovial tissues and TNF‐α-stimulated MH7A cells. Functionally, RAC2 knockdown suppressed proliferation, migration, and invasion while promoting apoptosis in TNF‐α-treated cells. 

Additionally, RAC2 downregulation mitigated oxidative stress and inflammatory cytokine secretion, indicating a protective effect against RA-associated cellular dysfunction. Further mechanistic analysis revealed that METTL3 enhanced RAC2 expression through m6A methylation, thereby activating the AKT signaling pathway. Notably, overexpression of RAC2 counteracted the effects of METTL3 knockdown, restoring RA-associated pathological features. Collectively, these findings highlight METTL3 as a key regulator of RA progression through m6A-dependent upregulation of RAC2, suggesting that targeting the METTL3/RAC2 axis could offer a novel therapeutic strategy for RA treatment.

Source: josr-online.biomedcentral.com/articles/10.1186/s13018-025-05526-4