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The present study investigated the potential protective effects of glutamine (GLU), glycine (GLY), methionine (MET), and leucine (LEU) in MTX-induced hepatorenal toxicity in vitro and in vivo. Freshly isolated hepatocytes and renal slices of rats were used to investigate the effect of these amino acids in vitro, while male Sprague\u2013Dawley rats were used to evaluate their effects in vivo. Rats were assigned into 6 equal groups: a negative control, MTX (20\u00a0mg\/kg\/day, i.p., 3\u00a0days), MTX\u2009+\u2009(GLU 25\u00a0mg\/kg\/day i.p., 6\u00a0days), MTX\u2009+\u2009(GLY 0.5 gm\/kg\/day, i.p., 3\u00a0days), MTX\u2009+\u2009(MET 1\u00a0mg\/kg\/day, i.p., 6\u00a0days) and MTX\u2009+\u2009LEU (50\u00a0mg\/kg\/day, i.p., 6\u00a0days). These amino acids showed enhanced viability of liver and kidney cells assessed by trypan blue exclusion and lactate dehydrogenase leakage tests, respectively. Besides, pre-incubation of suspended hepatocytes or renal slices with GLU (25\u00a0mM and 10\u00a0mM, respectively), GLY (25\u00a0mM and 5\u00a0mM, respectively), MET (12.5\u00a0mM and 5\u00a0mM, respectively) or LEU (25\u00a0mM and 10\u00a0mM, respectively), 30\u00a0min before MTX, significantly down-regulated caspase-3 and TNF-\u03b1 levels as compared with MTX-intoxicated groups. MTX-induced hepatorenal toxicity was manifested by increasing liver and kidney enzymes, oxidative stress and severe histopathological alterations. Amino acids pre-treatment abrogated MTX-induced alteration in hepatorenal toxicity indices as evidenced by amelioration in oxidative stress, inflammatory mediators, and histopathological changes. Amino acids may serve as a promising adjuvant therapy with MTX as it may ameliorate its hepatorenal toxicity through antioxidant, anti-inflammatory and anti-apoptotic mechanisms.<\/jats:p>","DOI":"10.1007\/s00210-026-05010-8","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T00:44:40Z","timestamp":1771202680000},"page":"11365-11388","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Amino acids protect against methotrexate-induced hepatorenal toxicity in vitro and in vivo"],"prefix":"10.1007","volume":"399","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2489-6342","authenticated-orcid":false,"given":"Basma M.","family":"Abdelaziz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisham A.","family":"Nematalla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ihab T.","family":"Abdel-Raheem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asser I.","family":"Ghoneim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,16]]},"reference":[{"key":"5010_CR1","doi-asserted-by":"publisher","DOI":"10.1155\/2017\/3281670","volume":"2017","author":"MM Abdel-Daim","year":"2017","unstructured":"Abdel-Daim MM, Khalifa HA, Abushouk AI, Dkhil MA, Al-Quraishy SA (2017) Diosmin attenuates methotrexate-induced hepatic, renal, and cardiac injury: a biochemical and histopathological study in mice. 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