Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation and joint destruction. Despite advances in understanding its pathogenesis, the role of epigenetic regulation and non-coding RNA networks remains inadequately explored. This study investigates the involvement of N6-methyladenosine (m6A) modification and circular RNA (circRNA), specifically circINTS4, in RA.    

We conducted a bibliometric analysis to map research trends in m6A and miR-146 family studies in RA. Whole-transcriptome sequencing was performed on synovial tissue from RA patients and healthy controls (HCs) to identify differentially expressed circRNAs. miRNA expression was profiled using publicly available datasets. The role of METTL3 in regulating circINTS4 was examined through loss-of-function experiments in RA fibroblast-like synoviocytes (RA-FLS). A dual-luciferase reporter assay validated the direct interaction between circINTS4 and miR-146b-3p. Functional assays in RA-FLS and in vivo models assessed the impact of circINTS4 depletion on disease progression.

circINTS4 was the most significantly downregulated circRNA in RA, and miR-146b-3p was the most upregulated miRNA in RA patients. METTL3 depletion in RA-FLS reduced global m6A methylation and decreased m6A enrichment on circINTS4, leading to increased circINTS4 expression and decreased miR-146b-3p levels. Clinical analysis revealed an inverse relationship between circINTS4 and miR-146b-3p expression. Functionally, circINTS4 served as a sponge for miR-146b-3p, with its depletion enhancing RA-FLS proliferation, migration, and resistance to apoptosis. In vivo, circINTS4 knockdown exacerbated synovial inflammation and elevated pro-inflammatory cytokine levels in a rat model of RA.

This study establishes a novel epitranscriptomic-circRNA regulatory axis in rheumatoid arthritis, wherein METTL3-mediated m6Amodification destabilizes the protective circular RNA circINTS4, thereby unleashing miR-146b-3p to drive synovial inflammation and joint destruction. By integrating multi-omics profiling with functional validation, we demonstrate that circINTS4 acts as a critical molecular brake on FLS pathogenicity and M1 macrophage polarization—a checkpoint that is epigenetically erased during RA progression. Importantly, circINTS4 exhibits superior diagnostic performance (AUC = 0.902) compared to conventional linear biomarkers, reflecting its exceptional stability and mechanistic relevance. These findings not only deepen our understanding of how RNA modifications orchestrate autoimmune pathogenesis but also position circINTS4 as a dual-purpose biomarker and therapeutic target. Restoring circINTS4 levels—either through METTL3 inhibition or direct circRNA delivery—represents a promising strategy to dampen chronic inflammation. Future efforts should focus on mapping the precise m6Areader proteins mediating circINTS4 decay, developing joint-targeting delivery systems, and validating circINTS4 as a liquid biopsy marker in large, longitudinal cohorts. Ultimately, targeting the METTL3/circINTS4/miR-146b-3p axis may offer a precision medicine approach to intercept RA at its epigenetic roots, transforming disease management from symptomatic control to mechanistic intervention.