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E3 ubiquitin ligases and deubiquitinases are crucial in IBD pathophysiology by modulating protein ubiquitination. This study investigated the regulatory role of a deubiquitinase ubiquitin\u2010specific peptidase 13 (USP13) in a\u00a0DSS\u2010induced colitis mouse model and explored the underlying mechanism. Intestinal epithelial\u2010specific\n                    <jats:italic>Usp13<\/jats:italic>\n                    \u00a0knockout (USP13\n                    <jats:sup>IEKO<\/jats:sup>\n                    ) mice were treated with\u00a0DSS to induce colitis. Adeno\u2010associated virus serotype 9 (AAV9) was constructed to overexpress UPS13 in colonic\u00a0tissues. The results show that intestinal epithelial\u2010specific USP13 knockout exacerbated DSS\u2010induced colitis, linked to increased ER stress and apoptosis. Mechanistically, USP13 interacted with\u00a0 GRP78, attenuating ER stress\u2010induced apoptosis and maintaining intestinal barrier integrity by selectively removing K63\u2010linked ubiquitin at lysine 327. Moreover, restoration of USP13 expression via AAV9 in USP13\n                    <jats:sup>IEKO<\/jats:sup>\n                    mice attenuated DSS\u2010induced colitis and preserved intestinal barrier integrity. Also, USP13 levels were\u00a0reduced in ulcerative colitis patients compared to the healthy controls, highlighting its protective role in intestinal health. These findings underscore the protective role of the USP13\u2010GRP78 axis in\u00a0IBD and suggest that targeting USP13 through intestinal epithelial\u2010specific gene therapy may be a potential therapeutic\u00a0strategy for IBD.\n                  <\/jats:p>","DOI":"10.1002\/advs.202500741","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T13:40:26Z","timestamp":1752846026000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Intestinal Epithelial\u2010Derived USP13 Alleviates Colonic Inflammation by Suppressing GRP78\u2010mediated Endoplasmic Reticulum Stress"],"prefix":"10.1002","volume":"12","author":[{"given":"Chenchen","family":"Qian","sequence":"first","affiliation":[{"name":"School of Pharmacy Hangzhou Normal University  Hangzhou Zhejiang 311121 China"},{"name":"Chemical Biology Research Center School of Pharmaceutical Sciences Wenzhou Medical University  Wenzhou Zhejiang 325035 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghong","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Pharmacy Hangzhou Normal University  Hangzhou Zhejiang 311121 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Pharmacy Hangzhou Normal University  Hangzhou Zhejiang 311121 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Medicine Hangzhou Normal University  Hangzhou Zhejiang 311121 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Hangzhou Normal University  Hangzhou Zhejiang 311121 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan","family":"Gan","sequence":"additional","affiliation":[{"name":"School of Pharmacy Hangzhou Normal University  Hangzhou Zhejiang 311121 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyang","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Hangzhou Normal University  Hangzhou Zhejiang 311121 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Joint Research Center on Medicine the Affiliated Xiangshan Hospital of Wenzhou Medical University  Ningbo Zhejiang 315700 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandr V.","family":"Samorodov","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Bashkir State Medical University  Ufa 450005 Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9347-4946","authenticated-orcid":false,"given":"Yi","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Pharmacy Hangzhou Normal University  Hangzhou Zhejiang 311121 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.09.019"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat7186"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v25.i38.5800"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1097\/MIB.0000000000000660"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.76"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/ibd\/izab191"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00810-9"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2022.01.006"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04566-6"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-023-01148-7"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI28746"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","unstructured":"R.Garcia\u2010Carbonell J.Wong J. 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