NR4A3 mediates Coal Dust Nanoparticle-induced Immunopathogenesis in Rheumatoid Arthritis

Coal miners with chronic coal dust exposure have elevated rheumatoid arthritis (RA) risk, yet the molecular mechanisms underlying this association remain poorly understood. Here we identify the orphan nuclear receptor NR4A3 as a central mediator linking coal dust nanoparticles (CD-NPs) to RA immunopathogenesis. Intranasal exposure of adjuvant-induced arthritis rats to CD-NPs for three weeks markedly exacerbates synovial inflammation and joint destruction in dose- and time-dependent manners. In primary synovial fibroblasts from RA patients, CD-NPs uptake induces a pathogenic phenotype characterized by enhanced migration, invasion, inflammatory cytokine and chemokine production, and impaired collagen synthesis. Mechanistically, NR4A3 stabilizes STAT3 dimers, thereby sustaining STAT3 signaling and promoting pathogenic activation of synovial fibroblasts. We further identify NR4A3 high synovial fibroblasts as a previously unrecognized immunopathogenic subpopulation associated with disease progression. In summary, our findings establish NR4A3 as a central pathogenic driver in coal dust-associated RA, positioning it as a promising therapeutic target.