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However, despite extensive research in targeted drug development for NLRP3, including MCC950, clinical success remains elusive. Here, we discovered that the activated NLRP3 inflammasome complex (disc-NLRP3) and the activating mutation L351P exhibited resistance to MCC950. Through investigations using the small-molecule compound polydatin, HSP90\u03b1 was found to stabilize both the resting (cage-NLRP3) and activated state (disc-NLRP3) of NLRP3 complexes, sustaining its activation. Our mechanistic studies revealed that polydatin specifically targets HSP90\u03b1, binding to it directly and subsequently interfering with the HSP90\u03b1-NLRP3 interaction. This disruption leads to the dissipation of cage-NLRP3, disc-NLRP3 complexes and NLRP3 L351P. Importantly, genetic and pharmacological inactivation of HSP90\u03b1 effectively reduced NLRP3 inflammasome activation and alleviated cerulein-induced acute pancreatitis. These therapeutic effects highlight the clinical potential of HSP90\u03b1 inhibition. Our findings demonstrate that HSP90\u03b1 is crucial for the stability of both the resting and activated states of the NLRP3 inflammasome during its sustained activation, and targeting HSP90\u03b1 represents a promising therapeutic strategy for diseases driven by the NLRP3 inflammasome.<\/jats:p>","DOI":"10.34133\/research.0551","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T20:47:08Z","timestamp":1733863628000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":12,"title":["Polydatin-Mediated Inhibition of HSP90\u03b1 Disrupts NLRP3 Complexes and Alleviates Acute Pancreatitis"],"prefix":"10.34133","volume":"7","author":[{"given":"Jiashu","family":"Yang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, \rNanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyang","family":"Jiao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, \rNanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nannan","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, \rNanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, \rNanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueyao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, \rNanjing University of Chinese Medicine, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, \rNanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingdong","family":"Kong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, \rNanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8506-3905","authenticated-orcid":true,"given":"Wenjie","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, \rNanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Department of Gastroenterology, Nanjing Drum Tower Hospital, School of Life Sciences, \rNanjing University, Nanjing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2024,12,17]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.01.022"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.2011.01046.x"},{"issue":"12","key":"e_1_3_3_4_2","doi-asserted-by":"crossref","DOI":"10.1083\/jcb.202006194","article-title":"The NLRP3-inflammasome as a sensor of organelle dysfunction","volume":"219","author":"Seoane PI","year":"2020","unstructured":"Seoane PI, Lee B, Hoyle C, Yu S, Lopez-Castejon G, Lowe M, Brough D. 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