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UK5099, a long\u2010established inhibitor of mitochondrial pyruvate carrier (MPC), is previously found to inhibit macrophage inflammatory responses independent of MPC expression. However, the mechanisms by which UK5099 inhibit inflammatory responses remain unclear. Here, it is shown that UK5099 is a potent inhibitor of the NLRP3 inflammasome in both mouse and human primary macrophages. UK5099 selectively suppresses the activation of the NLRP3 but not the NLRC4 or AIM2 inflammasomes. Of note, UK5099 retains activities on NLRP3 in macrophages devoid of MPC expression, indicating this inhibitory effect is MPC\u2010independent. Mechanistically, UK5099 abrogates mitochondria\u2010NLRP3 interaction and in turn inhibits the assembly of the NLRP3 inflammasome. Further, a single dose of UK5099 persistently reduces IL\u20101\u03b2 production in an endotoxemia mouse model. Importantly, structure modification reveals that the inhibitory activities of UK5099 on NLRP3 are unrelated to the existence of the activated double bond within the UK5099 molecule. Thus, this study uncovers a previously unknown molecular target for UK5099, which not only offers a new candidate for the treatment of NLRP3\u2010driven diseases but also confounds its use as an MPC inhibitor in immunometabolism studies.<\/jats:p>","DOI":"10.1002\/advs.202307224","type":"journal-article","created":{"date-parts":[[2024,7,1]],"date-time":"2024-07-01T05:05:47Z","timestamp":1719810347000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["UK5099 Inhibits the NLRP3 Inflammasome Independently of its Long\u2010Established Target Mitochondrial Pyruvate Carrier"],"prefix":"10.1002","volume":"11","author":[{"given":"Linyu","family":"Ran","sequence":"first","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine Shanghai East Hospital Tongji University  Shanghai 200120 China"},{"name":"Medical College Tongji University  Shanghai 200092 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