Background: Macrophage-driven synovitis is central to rheumatoid arthritis (RA) pathogenesis. The role of the RNA modification N6-methyladenosine(m ⁶ A) and its regulator WTAP in reprogramming synovial macrophages remains poorly understood. This study examines how the WTAP-m ⁶ A axis couples epitranscriptomic regulation to metabolic dysfunction, fueling inflammation in RA.

Objectives: Pro-inflammatory macrophages are central drivers of rheumatoid arthritis (RA) synovitis. m ⁶ A RNA modification regulates immune function, yet its specific role in pathogenic macrophage activation in RA is poorly defined. This study investigates how the m ⁶ A methyltransferase WTAP exacerbates disease through metabolic reprogramming.

Methods: Synovial macrophages from RA patients and healthy controls (HCs) were isolated for transcriptomic (RNA-seq), epitranscriptomic (MeRIP-seq), and metabolic analyses. Loss-of-function studies employed siRNA-mediated WTAP knockdown and the pharmacological m6A inhibitor 3-deazaadenosine (3-DA) in human macrophages. The therapeutic effect of 3-DA (intraperitoneal) or local Wtap knockdown was evaluated in collagen-induced arthritis (CIA) mice.

Results: RA macrophages exhibited a hyperinflammatory phenotype with elevated global m ⁶ A methylation and WTAP overexpression. Mechanistically, WTAP stabilized TNF and IL1B mRNAs via m ⁶ A, potentiating NF-κB signalling and secretion of TNF-α and IL-1β. Concurrently, WTAP enforced a profound glycolytic shift and induced mitochondrial dysfunction, a perturbation that triggered subsequent inflammatory activation. In the CIA model, both systemic 3-DA administration and local Wtapknockdown significantly attenuated arthritis severity, reduced synovitis, and improved mitochondrial function.

Conclusions: Our findings identify a pathogenic WTAP-m ⁶ A axis that links epitranscriptomic dysregulation in synovial macrophages to metabolic reprogramming and inflammatory activation, fuelling RA progression. Targeting this pathway presents a novel therapeutic strategy for RA.

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Acknowledgments: NIL.

Disclosure of Interests: None declared.