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In this study, we screened for pyroptotic inhibitors with the ultimate goal to benefit sepsis treatments. Accidentally, we identified that nitrosonisoldipine (NTS), a photodegradation product of calcium channel inhibitor nisoldipine, inhibits noncanonical pyroptosis. Using murine immortalized BM\u2010derived macrophage and human THP\u20101 cell line, we further discovered that NTS not only inhibits noncanonical pyroptosis mediated by caspase\u201011 or caspase\u20104 but also canonical pyroptosis mediated by caspase\u20101. Mechanistically, NTS directly inhibits the enzyme activities of these inflammatory caspases, and these inhibitory effects persist despite extensive washout of the drug. By contrast, apoptosis mediated by caspase\u20103\/\u20107 was not affected by NTS. Mice pretreated with NTS intraperitoneally displayed improved survival rate and extended survival time in LPS\u2010 and polymicrobe\u2010induced septic models, respectively. In conclusion, NTS is a selective inhibitor of inflammatory caspases that blocks both the noncanonical and canonical pyroptotic pathways. It is safe for intraperitoneal administration and might be used as a prototype to develop drugs for sepsis treatments.<\/jats:p>","DOI":"10.1002\/eji.202048937","type":"journal-article","created":{"date-parts":[[2021,1,17]],"date-time":"2021-01-17T11:24:35Z","timestamp":1610882675000},"page":"1234-1245","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Nitrosonisoldipine is a selective inhibitor of inflammatory caspases and protects against pyroptosis and related septic shock"],"prefix":"10.1002","volume":"51","author":[{"given":"Qianyue","family":"Chen","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Model Animals for Disease Study Model Animal Research Center State Key Laboratory of Pharmaceutical Biotechnology Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School Nanjing University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiashuo","family":"Zheng","sequence":"additional","affiliation":[{"name":"Helmholtz Zentrum M\u00fcnchen Institute of Metabolism and Cell Death  Neuherberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu GemPharmatech Co., Ltd.  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