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Despite its therapeutic efficacy, long term or high\u2010dose MTX treatment is associated with a significant risk of hepatotoxicity, leading to MTX\u2010induced liver injury (MTX\u2010LI). The pathogenesis of MTX\u2010LI involves multiple mechanisms, including oxidative stress, mitochondrial dysfunction, inflammation, and altered metabolic processes, which collectively contribute to hepatocellular damage and fibrosis. Clinically, MTX\u2010LI manifests as elevated liver enzymes, hepatic steatosis, and, in severe cases, cirrhosis, posing a challenge to treatment regimens. To mitigate MTX\u2010LI, a growing body of research has focused on exploring therapeutic and\/or preventive potential and pharmacological mechanisms of phytochemicals and pharmaceuticals. Phytochemicals, including flavonoids, terpenoids, alkaloids, and polyphenols, exhibit hepatoprotective effects attributed to their antioxidant, anti\u2010inflammatory, and antiapoptotic properties that can counteract MTX\u2010induced hepatic damage. Additionally, various pharmaceutical agents possessing antioxidants and anti\u2010inflammatory properties and favorably modulate metabolic pathways have shown promise in reducing the severity or progression of of MTX\u2010LI. The phytochemicals or pharmaceuticals showed beneficial in MTX\u2010LI primarily act by scavenging reactive oxygen species (ROS), modulating inflammatory pathways, and improving liver regeneration. Integrated together, its apparent that naturally occurring many phytochemicals as well as synthetic agents of pharmaceutical relevance are capable of preventing or alleviating MTX\u2010LI. However, the optimal strategies for integrating these agents into clinical practice require further investigations to highlight safety and efficacy in humans followed by pharmacological rationale of their possible use in therapeutics. Future directions should focus on elucidating the precise molecular mechanisms, establish safety and efficacy in humans, conducting regulatory toxicology studies and randomized clinical trials, and developing combination therapies for promotion as protective agents or adjuvants to maximize efficacy and minimize adverse effects.<\/jats:p>","DOI":"10.1155\/omcl\/9407932","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T07:07:20Z","timestamp":1775718440000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacological Mechanisms of Phytochemicals and Pharmaceutical Agents in Protecting Against Methotrexate\u2010Induced Liver Injury"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5564-2180","authenticated-orcid":false,"given":"Bushra","family":"Zia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mouza Hasan Alqaishi","family":"Alshehhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azimullah","family":"Sheikh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Mirza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4802-500X","authenticated-orcid":false,"given":"Sandeep B.","family":"Subramanya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7801-2966","authenticated-orcid":false,"given":"Shreesh K.","family":"Ojha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"e_1_2_13_1_2","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.4-4-340"},{"key":"e_1_2_13_2_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-06-292615"},{"key":"e_1_2_13_3_2","first-page":"125","article-title":"Methotrexate as a Single Agent and in Combination Chemotherapy for the Treatment of Non-Hodgkin\u2019s Lymphoma of Unfavorable Histology","volume":"65","author":"Canellos G. 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