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In this study, we found that 14-3-3\u03b5 facilitates NLRP3 inflammasome activation by enhancing NLRP3 K63 deubiquitination and promoting its translocation to the mitochondria-associated ER membranes (MAMs) for full activation. Mass spectrometry revealed that 14-3-3\u03b5 binds to NLRP3 in macrophages during sepsis. Plasma 14-3-3\u03b5 levels were elevated in patients with sepsis and were positively associated with disease severity. 14-3-3\u03b5 promoted NLRP3 inflammasome activation by facilitating NLRP3 aggregation and NLRP3\u2013ASC assembly. The interaction between 14-3-3\u03b5 and NLRP3 was dependent on phosphorylation at the S194 site of NLRP3 NACHT domain. The NLRP3\u201314-3-3\u03b5 interaction promoted K63 deubiquitination and enhanced the translocation of NLRP3 to MAMs, which is necessary for full activation of NLRP3 inflammasome. Furthermore, macrophage-conditional KO of 14-3-3\u03b5 or treatment with BV02, a 14-3-3 inhibitor, improved the survival rate and alleviated organ injuries in septic mice. Taken together, our data indicate that 14-3-3\u03b5 functions as a positive regulator of the NLRP3 inflammasome and could be a target for sepsis treatment.<\/jats:p>","DOI":"10.1172\/jci.insight.192970","type":"journal-article","created":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T19:00:49Z","timestamp":1767294049000},"source":"Crossref","is-referenced-by-count":3,"title":["14-3-3\u03b5\u2013dependent deubiquitination and translocation of NLRP3 activates the inflammasome during sepsis"],"prefix":"10.1172","volume":"11","author":[{"given":"Xingyu","family":"Li","sequence":"first","affiliation":[{"name":"Center for Infection and Immunity and Guangdong Provincial Engineering Research Center of Molecular Imaging, the Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siqi","family":"Ming","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Guangdong 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