{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:25:48Z","timestamp":1788582348774,"version":"build-2803163510"},"reference-count":80,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007471","name":"Northern Border University","doi-asserted-by":"publisher","award":["NBU-CRP-2026-1442"],"award-info":[{"award-number":["NBU-CRP-2026-1442"]}],"id":[{"id":"10.13039\/501100007471","id-type":"DOI","asserted-by":"publisher"}]},{"award":["NBU-CRP-2026-1442"],"award-info":[{"award-number":["NBU-CRP-2026-1442"]}],"id":[{"id":"https:\/\/ror.org\/03j9tzj20","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) is driven by oxidative stress, chronic inflammation, and disruption of cytoprotective signaling pathways. This study aimed to evaluate whether poly(lactic-co-glycolic acid) (PLGA)-based nanoparticle delivery enhances the chemoprotective efficacy of paeonol against 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis, with a focus on modulation of the NRF2\/HO-1 pathway. Sixty male Wistar rats were randomly assigned to six groups: control, paeonol (PNL), PNL-PLGA, DMH, DMH + PNL, and DMH + PNL-PLGA. CRC was induced using DMH over 10 weeks. Serum tumor biomarkers (AFP, CEA, CA19-9, CA125, CA15-3), oxidative stress markers (ROS, MDA, antioxidant enzymes), inflammatory cytokines, DNA damage, apoptosis- and autophagy-related gene expression, and hepatic and renal function were assessed. Histopathological and ultrastructural analyses of colonic tissues were performed. DMH exposure was markedly associated with increased tumor biomarkers, oxidative stress, and inflammatory mediators, DNA damage, and impaired liver and kidney function. It was also associated with the restoration of NRF2\/HO-1 signaling, improved redox balance, suppression of inflammation, reduction in DNA damage, and preservation of regulated NRF2\/HO-1 signaling, antioxidant defenses, autophagy markers, and apoptotic proteins, as well as severe histological and ultrastructural alterations. Free paeonol partially attenuated these changes. In contrast, PNL-PLGA was significantly associated with restoring NRF2\/HO-1 signaling, improving redox balance, suppressing inflammation, reducing DNA damage, and preserving colonic architecture and ultrastructure. These findings demonstrate that a PLGA-based nanoformulation of paeonol markedly improves its chemopreventive efficacy against DMH-induced CRC, primarily by activating NRF2\/HO-1 signaling and modulating oxidative stress, inflammation, apoptosis, and autophagy, highlighting its potential as a promising nanotherapeutic strategy for colorectal cancer.<\/jats:p>","DOI":"10.3390\/ijms27135673","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"5673","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Paeonol-Loaded PLGA Nanoparticles Attenuate DMH-Induced Colorectal Carcinogenesis-Associated Oxidative Stress, Inflammation, and Cellular Dysregulation via Modulation of NRF2\/HO-1 Signaling in Rats"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1855-843X","authenticated-orcid":false,"given":"M.","family":"Alfawaz","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekramy M.","family":"Elmorsy","sequence":"additional","affiliation":[{"name":"Center for Health Research, Northern Border University, Arar 73213, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0057-5672","authenticated-orcid":false,"given":"Ahmad Najem","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, College of Applied Medical Sciences, Northern Border University, Arar 91431, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2948-5040","authenticated-orcid":false,"given":"Eida M.","family":"Alshammari","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Sciences, University of Ha\u2019il, Ha\u2019il 2440, Saudi Arabia; eida.alshammari@uoh.edu.sa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-5994","authenticated-orcid":false,"given":"Mai A.","family":"Salem","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2924-9670","authenticated-orcid":false,"given":"Gehad E.","family":"Elshopakey","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1252-8403","authenticated-orcid":false,"given":"Manal S.","family":"Fawzy","sequence":"additional","affiliation":[{"name":"Center for Health Research, Northern Border University, Arar 73213, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagwa M.","family":"Aly","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","first-page":"89","article-title":"Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors","volume":"14","author":"Rawla","year":"2019","journal-title":"Prz. 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