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Using artificial intelligence\u2010guided analysis of a synovial single\u2010cell transcriptomic dataset, we identify O\u2010GlcNAc transferase (OGT) as a key regulator enriched in RA\u2010FLSs. Gain\u2010 and loss\u2010of\u2010function studies demonstrate that OGT is necessary to drive aggressive FLS phenotypes and exacerbate experimental arthritis. Mechanistically, OGT\u2010mediated O\u2010GlcNAcylation stabilizes SAP130, promoting histone deacetylation at the BTG2 promoter. This facilitates the deposition of repressive histone methylation marks, leading to BTG2 epigenetic silencing and ultimately fueling FLS aggression. To translate this mechanistic insight, we develop an FLS\u2010targeted proteolysis\u2010targeting chimera (PROTAC) by conjugating the OGT inhibitor OSMI\u20101 to the AS1411 aptamer, which selectively binds surface nucleolin (NCL) overexpressed on pathogenic FLSs and, upon internalization, employs NCL as a molecular bridge to recruit the E3 ligase MDM2 for cell\u2010selective OGT degradation. This PROTAC suppresses FLS pathogenicity, attenuates arthritis in mice, and demonstrates additive therapeutic benefit when combined with the TNF\u2010\u03b1 inhibitor etanercept. Collectively, our work establishes a translational paradigm that progresses from AI\u2010driven target discovery and mechanistic elucidation to the rational design of a cell\u2010type\u2010specific degradation therapy, offering a strategy to overcome the stromal\u2010driven therapeutic barrier in RA.<\/jats:p>","DOI":"10.1002\/advs.77466","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:27:14Z","timestamp":1788175634000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010Technique Integration Identifies O\u2010GlcNAc Transferase in Fibroblast\u2010Like Synoviocytes as a Therapeutic Target for Rheumatoid Arthritis"],"prefix":"10.1002","author":[{"given":"Duoli","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Systems Biology School of Life Sciences Southern University of Science and Technology  Shenzhen China"},{"name":"Institute of Integrated 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