The aim of the study was to investigate the role of N6-Methyladenosine (m6A) modification in the progression of rheumatoid arthritis (RA).Peripheral blood mononuclear cells (PBMCs) from RA patients and healthy controls were collected. The expression of m6A-modification related proteins and m6A levels were detected using PCR, western blot and m6A ELISA. The roles of methyltransferase-like 14 (METTL14) in the regulation of inflammation in RA was explored using MeRIP-sequencing and RNA immunoprecipitation assays. Collagen antibody-induced arthritis (CAIA) mice were used as an in vivo model to study the role of METTL14 in the inflammation progression of RA.We found that m6A writer METTL14 and m6A levels were decreased in PBMCs of active RA patients, and correlated negatively with the disease activity score using 28 joint counts (DAS28). Knockdown of METTL14 down-regulated m6A, and promoted the secretion of inflammatory cytokines IL-6 and IL-17 in PBMCs of RA patients. Consistently, METTL14 knockdown promoted joint inflammation accompanied by upregulation of IL-6 and IL-17 in CAIA mice. MeRIP-sequencing and functional studies confirmed that tumor necrosis factor alpha induced protein 3 (TNFAIP3), a key suppressor of NF-κB inflammatory pathway, was involved in m6A-regulated PBMCs. Mechanistic investigations revealed that m6A affected TNFAIP3 expression by regulation of mRNA stability and translocation in TNFAIP3 protein-coding regions (CDS).Our study highlights the critical roles of m6A on regulation of inflammation in RA progression. Treatment strategies targeting m6A modification may represent a new option for management of RA. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.