{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:07:18Z","timestamp":1790532438778,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"VCU Center"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>As a bona fide \u201cmaster switch,\u201d NOD-like receptor family pyrin domain containing 3 (NLRP3) functions not only as an inflammatory mediator but also as a primary sensor of metabolic stress and danger signals. Its dysregulation has been implicated in an exceptionally broad spectrum of human diseases, making it one of the most intensively studied therapeutic targets. While the discovery of the first direct antagonist MCC950 marked a turning point, the subsequent explosion of diverse inhibitor classes demands a systematic, up-to-date evaluation. This review comprehensively analyzes the current landscape of direct NLRP3 inhibitors, focusing on how recent structural breakthroughs illuminate specific mechanism-of-action differences. We systematically reviewed peer-reviewed literature from 2015 to 2026, categorizing small-molecule inhibitors based on their chemical scaffolds and binding pockets as revealed by cryo-EM and X-ray crystallography data. By mapping these structural insights into functional outcomes, we provide a definitive molecular-level analysis designed to guide the rational design and optimization of next-generation NLRP3-targeted therapeutics.<\/jats:p>","DOI":"10.3390\/ph19071104","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:47:32Z","timestamp":1784508452000},"page":"1104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deconstructing the Master Switch: Advances in Direct NLRP3 Inhibition"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5533-1747","authenticated-orcid":false,"given":"Yiming","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasha","family":"Murphy","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev.immunol.021908.132715","article-title":"The inflammasomes: Guardians of the body","volume":"27","author":"Martinon","year":"2009","journal-title":"Annu. 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