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However, the specific mechanisms underlying the effects of chicoric acid on dextran sulfate sodium (DSS)\u2010induced colitis remain unclear. Here, we aimed to elucidate the molecular mechanisms underlying the protective effects of chicoric acid in DSS\u2010induced colitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Mice with DSS\u2010induced colitis (UC mice) were treated for a week with chicoric acid. Symptoms of colitis, colonic pathology, inflammation\u2010related indicators, and intestinal mucosal barrier function were evaluated. RNA sequencing was performed on colon tissues to obtain differentially expressed genes. The deubiquitinating enzyme USP9X was selected, and the inhibitory and targeting effects of chicoric acid on USP9X were subsequently determined. In vivo and in vitro, DSS\u2010induced colitis was treated with USP9X inhibitors WP1130 and EOAI3402143. Ubiquitination label\u2010free quantitative proteomic analysis was performed to identify protein peptides that may undergo de\u2010ubiquitination by USP9X. Co\u2010immunoprecipitation (Co\u2010IP), immunohistochemistry and western blotting were used to validate in vivo and in vitro results.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Chicoric acid significantly alleviated clinical activity and histological changes, inhibited pro\u2010inflammatory cytokine production and improved integrity of the intestinal barrier in UC mice. Moreover, chicoric acid suppressed USP9X expression in colonic tissues from UC mice. Furthermore, USP9X contributed to promoting the onset of UC and that insulin\u2010like growth factor 2 mRNA\u2010binding protein 2 (IGF2BP2) was deubiquitinated by USP9X.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Chicoric acid ameliorated DSS\u2010induced colitis by targeting the USP9X\/IGF2BP2 axis, indicating that targeting the USP9X\/IGF2BP2 axis presents a promising and innovative therapeutic approach for the treatment of UC.<\/jats:p><\/jats:sec><jats:sec><jats:title>LINKED ARTICLES<\/jats:title><jats:p>This article is part of a themed issue Drugs and Drug Targets in Metabolic and Chronic Inflammatory Diseases. To view the other articles in this section visit <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v182.20\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17354","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T05:00:05Z","timestamp":1729573205000},"page":"4968-4983","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Chicoric acid exerts therapeutic effects in DSS\u2010induced ulcerative colitis by targeting the USP9X\/IGF2BP2 axis"],"prefix":"10.1111","volume":"182","author":[{"given":"Wei","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Gastroenterology Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunan","family":"Shan","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Surgery Affiliated Hospital of Shandong University of Traditional Chinese Medicine  Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics and National Clinical Research Center for Geriatrics, West China Hospital Sichuan University  Chengdu Sichuan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ri","family":"Sa","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,10,22]]},"reference":[{"key":"e_1_2_12_2_1","first-page":"406","article-title":"Ulcerative colitis: Rapid evidence review","volume":"105","author":"Adams S. 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