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Although the E3 ubiquitin ligase RNF31 is upregulated in IBD, its pathogenic mechanisms remain incompletely understood. To address this, a combination of in\u00a0vitro and in\u00a0vivo methods was employed. In\u00a0vitro, lipopolysaccharide (LPS)\u2010stimulated cell models were used to analyze transcription factor EB (TFEB) phosphorylation, its interaction with RNF31, ubiquitination, and subcellular localization. In\u00a0vivo, a DSS\u2010induced IBD mouse model was used to assess intestinal pathology, inflammation, and RNF31\u2010TFEB\u2010NLRP3 axis proteins after treatment with a novel synthetic curcumin analog (CM\u2010C1). We identified TFEB as a novel substrate of RNF31. LPS\u2010induced phosphorylation of TFEB promoted its binding to RNF31 (via TFEB\u2010S281\/T276 and RNF31\u2010K908), leading to TFEB ubiquitination, proteasomal degradation, suppressed autophagy, and subsequent NLRP3 inflammasome activation. The bioavailable TFEB activator CM\u2010C1 directly disrupted the RNF31\u2010TFEB interaction. This action promoted TFEB nuclear translocation, restored autophagic flux, alleviated intestinal inflammation in\u00a0vitro and in\u00a0vivo, and beneficially remodeled the gut microbiota. Our study unveils the RNF31\u2010TFEB\u2010NLRP3 axis as a pivotal pathogenic pathway in IBD and nominates CM\u2010C1, which targets this axis, as a promising multimodal therapeutic candidate.<\/jats:p>","DOI":"10.1002\/fsn3.71916","type":"journal-article","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T09:57:18Z","timestamp":1779530238000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the\n                    <scp>RNF31<\/scp>\n                    \u2013\n                    <scp>TFEB<\/scp>\n                    \u2013\n                    <scp>NLRP3<\/scp>\n                    Axis With a Curcumin Analog to Restore Autophagy and Alleviate Intestinal Inflammation"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6520-6083","authenticated-orcid":false,"given":"Lu","family":"Han","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital The First Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Postdoctoral Research Station, The First Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Jiangxi Provincial Key Laboratory of Digestive Diseases, Jiangxi Clinical Research Center for Gastroenterology, Digestive Disease Hospital The First Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang Jiangxi China"},{"name":"Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research The Seventh Affiliated Hospital, Sun Yat\u2010Sen University  Shenzhen Guangdong People's Republic of 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