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Epi\u2010berberine (EPI), an alkaloid from\n                    <jats:italic>Coptidis Rhizoma<\/jats:italic>\n                    , shows potential for UC treatment. This study aimed to assess EPI's effect on UC and explore the mechanism underlying its UC\u2010alleviating effect. The therapeutic effects of EPI on UC were validated in dextran sulfate sodium (DSS)\u2010induced colitis mice and lipopolysaccharide (LPS)\u2010induced Caco\u20102 inflammatory models and further investigated the underlying mechanism. In\u00a0vivo, high\u2010dose EPI (200\u2009mg\/kg) attenuated weight loss, reduced disease activity index, increased colon length, lowered colon macroscopic\/histological scores, restored intestinal mucosal barrier and inhibited colonic inflammation. EPI (25\/50\u2009\u03bcM) had similar in\u00a0vitro effects. mRNA\u2010seq identified EPI\u2010regulated genes in UC mice, revealing six gene clusters with analogous expression patterns. The largest cluster contained genes upregulated by DSS but downregulated by EPI, potentially involved in the MAPK pathway. Key DEGs were enriched in PI3K\u2010Akt and MAPK pathways, verified in\u00a0vivo and in\u00a0vitro. Literature retrieval and molecular docking predicted glutaminyl\u2010peptide cyclotransferase (QPCT) as EPI's potential UC therapeutic target. EPI inhibited DSS\/LPS\u2010induced QPCT upregulation in\u00a0vivo and in\u00a0vitro; QPCT knockdown suppressed inflammation and preserved Caco\u20102 monolayer barrier function, while QPCT overexpression reversed EPI's therapeutic effects. QPCT mediates PI3K\u2010Akt\/MAPK activation, and its overexpression abrogated EPI's inhibitory effects. EPI alleviates murine UC by protecting the intestinal mucosal barrier and inhibiting inflammation, likely via regulating the QPCT\u2010PI3K\u2010Akt\/MAPK pathway. It provides a preclinical basis for developing prophylactic strategies for inflammatory bowel disease.\n                  <\/jats:p>","DOI":"10.1002\/ptr.70300","type":"journal-article","created":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T10:11:16Z","timestamp":1773310276000},"page":"3009-3026","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Epi\u2010Berberine Alleviates Ulcerative Colitis, Protects the Intestinal Mucosal Barrier, and Inhibits Colonic Inflammation via Glutaminyl\u2010Peptide Cyclotransferase in a Mouse Model of\n                    <scp>DSS<\/scp>\n                    \u2010Induced Colitis"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4213-1829","authenticated-orcid":false,"given":"Bingyu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Geriatrics The First Affiliated Hospital of Henan University of Chinese Medicine  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