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The natural product oridonin possesses a novel mechanism for NLRP3 inhibition and a unique binding mode with NLRP3, but its poor anti\u2010inflammatory activity limits further application. After virtual screening of diverse natural product libraries, dehydrocostus lactone (DCL) was considered as a potential NLRP3 inhibitor. DCL effectively inhibited caspase\u20101 cleavage and release of IL\u20101\u03b2 in mouse and human macrophages at an extremely low concentration of 10\u00a0nM, comparable to MCC950. Mechanistically, our study assigned DCL a novel role in disrupting NLRP3 inflammasome assembly and ASC oligomerization. Excluding the influence on potassium\/chloride ion efflux, calcium ion influx, and production of mitochondrial ROS, DCL formed a covalent bond with cysteine 280 in NACHT domain of NLRP3, thereby inhibiting the interaction between NLRP3 and NEK7. Furthermore, DCL exhibited protective effects in mouse models of NLRP3 inflammasome\u2010mediated diseases, including dextran sulfate sodium\u2010induced colitis, 2,4,6\u2010trinitrobenzenesulfonic acid\u2010induced Crohn's disease, LPS\u2010induced septic shock, and monosodium urate\u2010induced peritonitis. Our findings identify NLRP3 as the direct target of DCL, positioning DCL as a promising lead compound for treatment of NLRP3 inflammasome\u2010related diseases.<\/jats:p>","DOI":"10.1002\/mco2.70367","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T06:38:48Z","timestamp":1756967928000},"source":"Crossref","is-referenced-by-count":7,"title":["Dehydrocostus Lactone Effectively Alleviates Inflammatory Diseases by Covalently and Irreversibly Targeting NLRP3"],"prefix":"10.1002","volume":"6","author":[{"given":"Qi","family":"Lv","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory of Functional Substance of Chinese Medicine School of Pharmacy Nanjing University of Chinese Medicine  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yishu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Functional Substance of Chinese Medicine School of Pharmacy Nanjing University of 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