{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:48:07Z","timestamp":1785415687440,"version":"3.56.0"},"reference-count":86,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Princess Nourah bint Abdulrahman University through the Researchers Supporting Project","award":["PNURSP2026R167"],"award-info":[{"award-number":["PNURSP2026R167"]}]},{"award":["PNURSP2026R167"],"award-info":[{"award-number":["PNURSP2026R167"]}],"id":[{"id":"https:\/\/ror.org\/05b0cyh02","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Ulcerative colitis (UC) is a chronic inflammatory disorder associated with cytokine imbalance, epigenetic alterations, and metabolic\u2013redox dysfunction. Despite the widespread use of mesalazine (5-ASA), therapeutic limitations remain. Norcantharidin (NCTD), a synthetic cantharidin analogue, may provide multi-target protection against UC. Experimental colitis was induced in male Sprague-Dawley rats by intrarectal administration of 4% acetic acid (AA). Rats received oral NCTD (10 mg\/kg), 5-ASA (100 mg\/kg), or their combination for 8 days. Disease severity was assessed by disease activity index, body weight, colon length, colon weight\/length ratio, and histopathology. Colonic biomarkers were evaluated using ELISA, qRT-PCR, Western blotting, and immunohistochemistry. Fe2+ and malondialdehyde (MDA) were measured as indicators of iron accumulation and lipid peroxidation. Molecular docking suggested that NCTD may adopt plausible binding poses within the binding pockets of AMPK, SIRT1, and DNMT1, providing structural support for potential protein\u2013ligand interactions. NCTD significantly ameliorated AA-induced colitis, improving clinical and histological outcomes. These effects were associated with reduced IL-6, TNF-\u03b1, DNMT1, Fe2+, and MDA levels, restoration of SOCS3, activation of p-AMPK\/SIRT1\/FOXO3a signaling, and enhancement of Nrf2\/HO-1 defenses. Combined NCTD\/5-ASA treatment produced greater clinical and histological protection, with differential effects on molecular markers. Docking studies suggested favorable interactions of NCTD with AMPK, SIRT1, and DNMT1. NCTD treatment was associated with protection against experimental colitis, linked to modulation of inflammatory, epigenetic, metabolic, and antioxidant pathways.<\/jats:p>","DOI":"10.3390\/ijms27156666","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T09:47:41Z","timestamp":1785145661000},"page":"6666","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Norcantharidin Ameliorates Experimental Ulcerative Colitis Through Epigenetic and Metabolic Reprogramming Involving IL-6\/DNMT1\/SOCS3 and AMPK\/SIRT1\/FOXO3a-Nrf2 Signaling"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8964-458X","authenticated-orcid":false,"given":"Eman H.","family":"Yousef","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Biochemistry (Biochemistry), Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samia S.","family":"Hawas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-5626","authenticated-orcid":false,"given":"Mohamed M.","family":"Salama","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mostafa E.","family":"Metawee","sequence":"additional","affiliation":[{"name":"Department of Histology, Faculty of medicine (Boys), Al-Azhar University, Cairo 11651, Egypt"},{"name":"Department of Histology, General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2917-2423","authenticated-orcid":false,"given":"Hader I.","family":"Sakr","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Faculty of Medicine, Cairo University, Cairo 12613, Egypt"},{"name":"Department of Physiology, General Medicine Practice Program, Department of Medical Physiology, Batterjee Medical College, Jeddah 21442, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3144-8305","authenticated-orcid":false,"given":"Sumaiah J.","family":"Alarfaj","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1178-7005","authenticated-orcid":false,"given":"Amany A.","family":"Alzokaky","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo 11651, Egypt"},{"name":"Department of Pharmacology and Biochemistry (Pharmacology), Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"112541","DOI":"10.1016\/j.intimp.2024.112541","article-title":"Repurposing metformin as adjuvant therapy in patients with ulcerative colitis treated with mesalamine: A randomized controlled double-blinded study","volume":"138","author":"Hegazy","year":"2024","journal-title":"Int. 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