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This study aimed to assess the pivotal role of USP1-associated factor 1 (UAF1) in colitis. UC was induced in male C57BL\/6 mice using 2.0% dextran sulfate sodium (DSS). In an in vitro model, RAW264.7 cells were exposed to 200 ng\/ml of LPS\u2009+\u2009ATP. UAF1 expression level was evaluated in colonic tissues, macrophages, and serum samples using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The study assessed weight, disease activity index (DAI) score, myeloperoxidase (MPO) activity, crypt length, inflammatory factors, and epithelial cell function in a mouse model of colitis treated with a UAF1 inhibitor. Microarray analysis identified potential UAF1 targets. Gene interference investigated NLR family pyrin domain containing 3 (NLRP3) involvement in UAF1-induced colitis inflammation. Immunoprecipitation, ubiquitination, and luciferase assays examined the effects of methyltransferase-like 3 (METTL3) methylation on the expression levels of NLRP3 and UAF1.  UAF1 expression level was upregulated in colon tissues, RAW264.7 macrophages, and serum samples of colitis mice (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). The UAF1 inhibitor (ML-323) enhanced weight and reduced DAI score in colitis mice (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). It also decreased MPO activity and ulcer area, and restored crypt length (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). UAF1 inhibitor improved epithelial cell function by suppressing NLRP3 activity (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). UAF1 promoted inflammation in RAW264.7 macrophages via NLRP3 inflammasome induction (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01). UAF1 modulated NLRP3 protein expression, leading to reduced NLRP3 ubiquitination induced by LPS\u2009+\u2009ATP. The m6A-forming enzyme METTL3 enhanced UAF1 stability (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.01) to facilitate UAF1 expression. The findings suggested that METTL3, as an m6A-forming enzyme, could regulate UAF1 mRNA, promoting inflammation in colitis through NLRP3 induction. Inhibiting UAF1 emerges as a potential therapeutic strategy for colitis.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1038\/s41598-025-88435-0","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T08:54:29Z","timestamp":1739868869000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["N6-methyladenosine (m6A)-forming enzyme METTL3 controls UAF1 stability to promote inflammation in a model of colitis by stimulating NLRP3"],"prefix":"10.1038","volume":"15","author":[{"given":"Yongqiang","family":"Lai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiancheng","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"88435_CR1","doi-asserted-by":"crossref","unstructured":"Liu, J. et al. 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All methods are reported in accordance with ARRIVE guidelines. All experimental protocols were approved by the Ethics Committee of the second general hospital of Guangdong Province.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All authors consent to participate.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"All authors have given consent to publish.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}],"article-number":"5876"}}