Cerium Nanoparticle-Mediated Inhibition of the NSUN2/m⁵C Axis Suppresses Synovial Aggression in Rheumatoid Arthritis

Rheumatoid arthritis (RA) involves persistent synovial inflammation and progressive destruction of cartilage and bone, where aberrantly activated fibroblast-like synoviocytes (FLSs) play a central role. Although 5-methylcytosine (m⁵C) modification is implicated in many diseases, its role in RA remains unclear. Here, we observed upregulated expression of the m⁵C methyltransferase NOP2/Sun domain family member 2 (NSUN2) in both synovial tissues (STs) and FLSs from RA patients. Functionally, NSUN2 knockdown suppressed migration and invasion of RA FLSs, whereas NSUN2 overexpression exerted opposing effects. Mechanistically, NSUN2 mediated m⁵C modification of isoprenylcysteine carboxyl methyltransferase (ICMT) mRNA and enhanced its stability. Furthermore, we identified salvianolic acid A (SAA) as an NSUN2 inhibitor, which phenocopied the effects of NSUN2 knockdown on RA FLSs. Given the well-recognized ROS-scavenging capacity of cerium oxide nanoparticles, we constructed Ce/SAA nanoparticles (Ce/SAA NPs) via coordination self-assembly to enable synergistic therapy for RA. Notably, Ce/SAA NPs ameliorated arthritis in collagen-induced arthritis (CIA) mice, and intra-articular NSUN2-siRNA attenuated disease progression in CIA rats. These results highlight NSUN2‑mediated m⁵C modification in RA pathogenesis and suggest NSUN2 as a therapeutic target.