snoRNA <i>Snord3</i> promotes rheumatoid arthritis by epigenetic regulation of ESM1 in fibroblast-like synoviocytes in mice

Rheumatoid arthritis (RA) is a chronic autoimmune condition characterized by aggressive fibroblast-like synoviocytes (FLSs). Small nucleolar RNAs (snoRNAs), traditionally implicated in ribosome biogenesis, are now recognized as disease regulators. However, their involvement in RA-FLSs remains poorly understood. Here, we identified <i>small nucleolar RNA, C/D box 3</i> (<i>SNORD3</i>), a specific snoRNA up-regulated by tumor necrosis factor-α and interleukin-17, as a key driver of the aggressive transformation of RA-FLSs in vitro. Using an FLS-specific aptamer-functionalized siRNA delivery system, we demonstrated that silencing <i>Snord3</i> alleviated arthritic symptoms in collagen-induced arthritis (CIA) mice. Transcriptome analyses revealed that <i>SNORD3</i> up-regulated endothelial cell-specific molecule 1 (ESM1) by modulating the polycomb repressive complex 2 (PRC2)-mediated trimethylation of histone H3 at lysine-27 (H3K27me3), driving the aggressive transformation of RA-FLSs. Mechanistically, we found that <i>SNORD3</i> physically interacted with enhancer of zeste homolog 2 (EZH2) and competitively disrupted the association of EZH2 with retinoblastoma binding protein 4 within PRC2, thus diminishing the H3K27me3 mark on the <i>ESM1</i> gene promoter to relieve the transcriptional repression of <i>ESM1</i>. We screened an ESM1-specific aptamer 04 (ESMA04) by systematic evolution of ligands by exponential enrichment, which neutralized ESM1 and inhibited the aggressive transformation of RA-FLSs in vitro. When administered either alone or in combination with a biologic disease-modifying antirheumatic drug, etanercept, ESMA04 demonstrated therapeutic efficacy in CIA mice. Overall, our findings identified <i>SNORD3</i>-EZH2-ESM1 signaling as a driver of RA-FLS pathogenesis and underscored the promise of aptamer-based therapies for RA treatment.