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Activation is controlled by two sequential steps: a priming step, followed by an assembly step. Nrf2 has been shown to promote NLRP3 inflammasome activation; however, the underlying mechanisms remain elusive. This study identifies Nrf2 as an encourager of NLRP3 inflammasome activation. We show that Nrf2 inhibition suppresses NLRP3 inflammasome activation in macrophages, including THP-1 cells and BMDMs. In addition, Nrf2 facilitates NLRP3 inflammasome assembly. Mechanically, Nrf2 increases Klf9 expression by binding to the Klf9 promoter. Klf9 stabilizes TXNIP by deubiquitination, thereby enhancing the TXNIP-NLRP3 interaction, which is required for NLRP3 inflammasome assembly and full activation. Finally, Nrf2 deficiency exerts a protective effect and alleviates NLRP3 inflammasome activation in mouse models of DSS-induced colitis and MSU crystals-induced acute gouty arthritis. Our study reveals a novel regulatory mechanism of NLRP3 inflammasome by Nrf2 and indicates Nrf2 may be a promising target for treating NLRP3 inflammasome-driven diseases.<\/jats:p>","DOI":"10.1038\/s41420-026-03219-3","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T16:36:32Z","timestamp":1782491792000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nrf2 promotes NLRP3 inflammasome assembly and activation by Klf9-TXNIP axis"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7288-3366","authenticated-orcid":false,"given":"You","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"You","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Yu","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang-Hua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Ping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4866-5267","authenticated-orcid":false,"given":"Ming-Cai","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4541-6865","authenticated-orcid":false,"given":"Su-Yu","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"3219_CR1","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1038\/s41586-019-1295-z","volume":"570","author":"H Sharif","year":"2019","unstructured":"Sharif H, Wang L, Wang WL, Magupalli VG, Andreeva L, Qiao Q, et al. 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