{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:37:38Z","timestamp":1792291058953,"version":"4.4.0"},"reference-count":70,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"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":["Biomolecules"],"abstract":"<jats:p>Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent, but its clinical utility is limited by oxidative stress-mediated renal toxicity. This study evaluated the nephroprotective potential of the dietary polyphenolic bioactive molecule piceatannol (PIC) in its crude and liposomal nanoparticle (PIC-LNP) forms against MTX-induced kidney injury in rats. Sixty rats were allocated into six groups and received vehicle, PIC, PIC-LNPs, MTX, or combinations of MTX with PIC or PIC-LNPs. MTX administration induced marked renal dysfunction and oxidative\/nitrosative stress, reflected by elevated serum urea, creatinine, and uric acid, together with increased renal ROS, MDA, protein carbonyls, 8-OHdG, and nitric oxide, in parallel with suppression of the Nrf2\/HO-1 antioxidant pathway. These disturbances were accompanied by activation of TLR4\/NF-\u03baB and MAPK signaling, upregulation of pro-inflammatory cytokines, and a shift toward apoptosis, as evidenced by increased Bax and caspase-3 and reduced Bcl-2 expression. Histological and ultrastructural analyses confirmed extensive glomerular and tubular damage with mitochondrial disruption and cytoplasmic vacuolations. PIC treatment attenuated these MTX-induced alterations, whereas the liposomal formulation conferred superior protection. PIC-LNPs restored Nrf2\/HO-1 signaling, enhanced endogenous antioxidant defenses, reduced oxidative\/nitrosative and inflammatory responses, and normalized apoptotic markers, accompanied by substantial preservation of renal architecture and cellular integrity. Immunohistochemistry demonstrated strong Nrf2 expression with minimal NF-\u03baB activation in the PIC-LNP group. Collectively, these findings highlight liposomal piceatannol as a promising bioactive-molecule-based strategy for controlling oxidative stress and mitigating chemotherapy-associated oxidative-stress-related renal injury.<\/jats:p>","DOI":"10.3390\/biom16040517","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:26:12Z","timestamp":1775121972000},"page":"517","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Liposomal Piceatannol Mitigates Methotrexate-Induced Oxidative Renal Injury via Modulation of Nrf2\/HO-1, TLR4\/NF-\u03baB, MAPK, and Apoptotic Pathways in Rats"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6160-5284","authenticated-orcid":false,"given":"Fahad","family":"Alshammari","sequence":"first","affiliation":[{"name":"Department of Biology, College of Science, Jouf University, Sakaka 72341, 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\/0009-0006-7577-1856","authenticated-orcid":false,"given":"Abdulrahman S.","family":"Aldaghmi","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Jouf University, Sakaka 72341, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahd","family":"Alaajam","sequence":"additional","affiliation":[{"name":"Department of Medical Laboratory Technology, College of Nursing and Health Science, Jazan University, Jazan 45142, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1504-4367","authenticated-orcid":false,"given":"Ahmed S.","family":"Shams","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia 41522, 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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4318-1329","authenticated-orcid":false,"given":"Nora","family":"Hosny","sequence":"additional","affiliation":[{"name":"Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","first-page":"905","article-title":"Efficacy of methotrexate as anti-inflammatory and anti-proliferative drug in dermatology: Three case reports","volume":"18","author":"Nedelcu","year":"2019","journal-title":"Exp. 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