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In this study, rats received MTX (30\u2009mg\/kg) with or without TMZ pretreatment (20\u2009mg\/kg). MTX caused a 2.7\u20133.6\u2010fold increase in serum transaminases, while TMZ pretreatment caused a 37%\u201340% reduction. Regarding oxidative markers, MTX significantly suppressed the antioxidant glutathione (GSH) levels by 37% and elevated malondialdehyde (MDA) levels by 29%, while TMZ boosted GSH levels by 40% and reduced MDA levels by 20%. Next, we assessed nuclear factor kappa B (NF\u2010\u03baB) (p\u201065), nuclear factor erythroid 2\u2010related factor 2 (Nrf2) and hemoxygenase\u20101 (HO\u20101) to find that MTX significantly elevated the levels of the proinflammatory nuclear factor kappa B (NF\u2010\u03baB) (p65) by 2.4\u2010fold, while TMZ pretreatment reduced its levels by 48%. Conversely, MTX decreased the levels of Nrf2, HO\u20101, and adenosine triphosphate (ATP) by 55%\u201371%, while TMZ led to a threefold increase in their levels. Regarding apoptosis, MTX caused a five to sixfold elevation in B\u2010cell lymphoma 2 associated X (Bax)\/B\u2010cell lymphoma 2 (BCL2) ratio and caspase\u20103, while TMZ pretreatment caused a threefold reduction in their levels. An in silico analysis of TMZ protein target\u2010prediction revealed statistically enriched pathways related to oxidative stress, inflammation, and apoptosis. In conclusion, pretreatment with TMZ successfully ameliorated MTX\u2010induced alterations in serum aminotransferases, liver histology, oxidative stress, and apoptosis. Pathway enrichment analysis (PEA) showed that TMZ is involved in multiple signaling and immune\u2010related pathways that might be, at least partly, implicated in its cytoprotective effects.<\/jats:p>","DOI":"10.1002\/ardp.202400726","type":"journal-article","created":{"date-parts":[[2025,4,2]],"date-time":"2025-04-02T04:43:18Z","timestamp":1743568998000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Trimetazidine mitigates methotrexate\u2010induced liver damage: Insights From biochemical, histological, and in silico analyses"],"prefix":"10.1002","volume":"358","author":[{"given":"Maha R. 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