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The Nod\u2010like receptor family pyrin domain\u2010containing 3 (NLRP3) inflammasome is an important regulatory factor in cellular pyroptosis that promotes the inflammatory response. Inhibitors targeting the NLRP3 inflammasome have emerged as promising potential therapeutic agents for inflammatory diseases. Through large\u2010scale screening, we found that the FDA\u2010approved drug CeeNU strongly inhibited NLRP3\u2010mediated pyroptosis. CeeNU exhibited dose\u2010dependent suppression of NLRP3 inflammasome activation and effectively mitigated inflammasome\u2010driven pyroptotic cell death in both human and murine macrophages\/microglia. Mechanistically, we further demonstrated that CeeNU specifically binds to arginine 335 within the NACHT domain of NLRP3, abrogating NLRP3 inflammasome activation by blocking its assembly. Importantly, CeeNU showed remarkable protective effects in multiple mouse models of NLRP3 inflammasome\u2010mediated diseases, including experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein (MOG), lipopolysaccharide (LPS)\u2010induced septic shock, monosodium urate (MSU)\u2010induced peritonitis, and MSU\u2010induced gouty arthritis. Our results demonstrate that CeeNU, a clinically available drug, acts as an NLRP3 inhibitor and holds therapeutic potential for NLRP3 inflammasome\u2010mediated pyroptotic diseases.<\/jats:p>","DOI":"10.1002\/mco2.70695","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T04:47:38Z","timestamp":1777006058000},"source":"Crossref","is-referenced-by-count":1,"title":["High\u2010Throughput Screening Reveals That CeeNU Acts as a New NLRP3 Inflammasome Inhibitor"],"prefix":"10.1002","volume":"7","author":[{"given":"Sen\u2010Lin","family":"Ji","sequence":"first","affiliation":[{"name":"Department of Neurology Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing China"},{"name":"State Key Laboratory of Pharmaceutical Biotechnology and Institute of Translational Medicine for Brain Critical Diseases Nanjing University  Nanjing China"},{"name":"Jiangsu Key Laboratory for Molecular Medicine Medical School of Nanjing 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