{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T07:25:57Z","timestamp":1786951557595,"version":"build-2736575974"},"reference-count":39,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Methotrexate (MTX) exerts cytotoxic effects primarily through folate pathway inhibition; however, increasing evidence suggests that MTX\u2010induced oxidative stress and mitochondrial apoptosis significantly contribute to cellular injury. The present study aimed to investigate MTX\u2010induced redox imbalance and intrinsic apoptotic activation in OVCAR\u20103 ovarian cancer cells and to evaluate whether sodium selenite, fucoidan, caffeic acid, and resveratrol differentially modulate redox and mitochondrial signaling pathways. OVCAR\u20103 cells were exposed for 24\u2009h to MTX (10\u2009\u00b5M) alone or in combination with sodium selenite (SS), fucoidan (FUC), caffeic acid (CA), or resveratrol (RSV). Oxidative stress parameters, including total antioxidant capacity (TAC), total oxidant capacity (TOC), oxidative stress index (OSI), and malondialdehyde (MDA) were measured. Redox signaling proteins (Nrf2 and HO\u20101) and intrinsic apoptotic markers (Bax, Bcl\u20102, cytochrome\u2010c, cleaved caspase\u20109, and cleaved caspase\u20103) were quantified by ELISA. MTX significantly decreased TAC while increasing TOC, OSI, and MDA levels, indicating marked oxidative imbalance. Concurrently, Nrf2 and HO\u20101 protein expression levels were significantly reduced. MTX also increased the Bax\/Bcl\u20102 ratio, increased cytochrome\u2010c protein levels, and elevated cleaved caspase\u20109 and caspase\u20103 levels, consistent with activation of intrinsic mitochondrial apoptotic signaling. Antioxidant co\u2010treatment partially restored redox balance and attenuated alterations in intrinsic apoptosis\u2010associated protein markers. Among the concentrations examined, resveratrol produced the largest modulatory effect. MTX induces redox\u2010dependent coordinated alterations in intrinsic apoptosis\u2010associated proteins in OVCAR\u20103 cells. Integrated evaluation of Nrf2 and HO\u20101 protein expression together with cytochrome\u2010c\u2013caspase signaling provides supportive evidence regarding MTX\u2010induced cellular stress responses. Selected antioxidants partially modulate this pathway, suggesting a regulatory role in redox\u2010associated chemotherapeutic stress.<\/jats:p>","DOI":"10.1002\/jbt.71073","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T05:39:51Z","timestamp":1786599591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Methotrexate Alters Nrf2\/HO\u20101 Protein Expression and Intrinsic Apoptosis\u2010Associated Protein Responses in OVCAR\u20103 Ovarian Cancer Cells: Differential Modulation by Antioxidant Compounds"],"prefix":"10.1002","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2923-5869","authenticated-orcid":false,"given":"Oya","family":"Korkmaz","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Faculty of Medicine Malatya Turgut \u00d6zal University Malatya 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