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Fifty male Wistar rats were divided into five groups: control, MTX, and three pretreatment groups receiving ESOM (30 mg\/kg), CANA (30 mg\/kg), or their combination. ESOM and CANA were administered for 8 days before and 1 day after a single MTX injection (20 mg\/kg, intraperitoneally) on day 9 to induce hepatotoxicity. Liver injury, oxidative stress, inflammation, and apoptosis were assessed using biochemical, histopathological, immunohistochemical, qRT-PCR, and western blot analyses. Data were analyzed by one-way analysis of variance (ANOVA) and Tukey\u2019s post hoc test, with significance at\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05. Results were presented as mean\u2009\u00b1\u2009standard error (SE). Rats that received MTX showed significant liver damage, marked by elevated ALT, AST, MDA, MPO, iNOS, TNF-\u03b1, IL-6, and IL-1\u03b2 levels (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01) and decreased antioxidant enzymes (HO-1, Nrf2, and GSH). Immunohistochemistry revealed increased NF-kB p65 and caspase-9 expression (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), correlating with histopathological changes. Pretreatment with ESOM and CANA reduced liver enzyme levels, improved histology, restored antioxidant balance, and inhibited inflammatory pathways via p38MAPK\/NF-kB p65 and JAK1\/STAT3 (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). Moreover, ESOM and CANA preserved PI3K\/Akt activity and prevented caspase-dependent apoptosis (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). Additionally, the combination treatment showed synergistic hepatoprotective effects, demonstrated by significant improvements in all measured parameters. These findings suggested that ESOM and CANA had significant potential as therapeutic agents for alleviating MTX-induced hepatotoxicity and warranted further investigation in future research.\n                  <\/jats:p>","DOI":"10.1007\/s00210-025-03908-3","type":"journal-article","created":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T13:07:52Z","timestamp":1741352872000},"page":"10901-10919","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Modulation of AMPK by esomeprazole and canagliflozin mitigates methotrexate-induced hepatotoxicity: involvement of MAPK\/JNK\/ERK, JAK1\/STAT3, and PI3K\/Akt signaling pathways"],"prefix":"10.1007","volume":"398","author":[{"given":"Ahmed M.","family":"El-Dessouki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed E.","family":"Kaml","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed F.","family":"EL-Yamany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,7]]},"reference":[{"key":"3908_CR1","doi-asserted-by":"publisher","unstructured":"Abdelall AMA, Khames A, Bekhit AA, Fathy MJI (2024) Potential effect of etoricoxib in reducing inflammation in methotrexate-induced pulmonary injury in rats: role of oxidative stress and the TLR4\/p38-MAPK\/NF-\u03baB signaling pathway. 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