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Transl. Med."],"published-print":{"date-parts":[[2025,11,12]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">small nucleolar RNA, C\/D box 3<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">SNORD3<\/jats:italic>\n                    ), a specific snoRNA up-regulated by tumor necrosis factor\u2013\u03b1 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\n                    <jats:italic toggle=\"yes\">Snord3<\/jats:italic>\n                    alleviated arthritic symptoms in collagen-induced arthritis (CIA) mice. Transcriptome analyses revealed that\n                    <jats:italic toggle=\"yes\">SNORD3<\/jats:italic>\n                    up-regulated endothelial cell\u2013specific molecule 1 (ESM1) by modulating the polycomb repressive complex 2 (PRC2)\u2013mediated trimethylation of histone H3 at lysine-27 (H3K27me3), driving the aggressive transformation of RA-FLSs. Mechanistically, we found that\n                    <jats:italic toggle=\"yes\">SNORD3<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">ESM1<\/jats:italic>\n                    gene promoter to relieve the transcriptional repression of\n                    <jats:italic toggle=\"yes\">ESM1<\/jats:italic>\n                    . 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\n                    <jats:italic toggle=\"yes\">SNORD3<\/jats:italic>\n                    -EZH2-ESM1 signaling as a driver of RA-FLS pathogenesis and underscored the promise of aptamer-based therapies for RA treatment.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adt5340","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T18:58:19Z","timestamp":1762973899000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":16,"title":["snoRNA\n                    <i>Snord3<\/i>\n                    promotes rheumatoid arthritis by epigenetic regulation of ESM1 in fibroblast-like synoviocytes in mice"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5995-0869","authenticated-orcid":true,"given":"Jie","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China."},{"name":"Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8208-9939","authenticated-orcid":true,"given":"Xuekun","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runrun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuqian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China."},{"name":"Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China."},{"name":"Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3840-0649","authenticated-orcid":true,"given":"Xinxin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyu","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Guanghua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2848-3329","authenticated-orcid":true,"given":"Chunhao","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China."},{"name":"Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong SAR 999077, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9273-0494","authenticated-orcid":true,"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4704-5141","authenticated-orcid":true,"given":"Yiying","family":"Liang","sequence":"additional","affiliation":[{"name":"Shenzhen LingGene Biotech Co. 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