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Acetaminophen (APAP) overdose remains one of the prominent contributors to hepato-renal damage. Aim: Our study assessed the novel effect of Cana against APAP-induced toxicities. Main methods: mice were randomized into five groups: negative control, Cana<jats:sub>25<\/jats:sub>, APAP, Cana<jats:sub>10<\/jats:sub>\u2009+\u2009APAP, and Cana<jats:sub>25<\/jats:sub>\u2009+\u2009APAP. Cana was given for 5 days; a single dose of APAP was injected on the 6<jats:sup>th<\/jats:sup> day, followed by the scarification of animals 24 h later. Key findings: Pre-treatment with Cana ameliorated hepatic and renal functions, whereas, on the molecular levels, Cana promoted hepatic\/renal <jats:italic>P<\/jats:italic>-AMP-activated protein kinase-\u03b1\/ protein kinase B (<jats:italic>p<\/jats:italic>-Akt)\/Glycogen synthase kinase (<jats:italic>p<\/jats:italic>-GSK3\u03b2) protein expression. Alternatively, Cana dampened the expression of STAT-3 and Fyn-kinase genes with a subsequent increase in the contents of suppressor of cytokine signaling (SOCS)-3 and also boosted the contents of the nuclear factor erythroid related factor 2 (Nrf-2)\/heme oxygenase (HO)-1\/ NADPH quinone oxidoreductase (NQO)-1 axis. The crosstalk between these paths ameliorated the APAP-induced hepatorenal structural alterations. Significance: Cana hepatorenal protective impact was provoked partly through modulating <jats:italic>p-<\/jats:italic>AMPK-\u03b1 \/SOCS-3\/STAT-3 and GSK3\u03b2\/Fyn-kinase signaling for its anti-inflammatory and antioxidant effects.<\/jats:p>","DOI":"10.1038\/s41598-024-82163-7","type":"journal-article","created":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T16:37:15Z","timestamp":1735922235000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Canagliflozin alleviates acetaminophen-induced renal and hepatic injury in mice by modulating the p-GSK3\u03b2\/Fyn-kinase\/Nrf-2 and p-AMPK-\u03b1\/STAT-3\/SOCS-3 pathways"],"prefix":"10.1038","volume":"15","author":[{"given":"Abeer","family":"Bishr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bassant M.","family":"El-Mokadem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa A.","family":"Gomaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,3]]},"reference":[{"key":"82163_CR1","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.2215\/CJN.11290821","volume":"17","author":"MA Perazella","year":"2022","unstructured":"Perazella, M. 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