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On the other hand, it exerts deleterious cellular effects in clinical applications as an antineoplastic agent, such as liver damage and cirrhosis. TAM-induced hepatic toxicity is mainly attributed to oxidative stress and inflammation. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-\u03b3) agonist, is utilized to treat diabetes mellitus type-2. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. This research assessed the impact of PIO against TAM-induced hepatic intoxication.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Rats received PIO (10\u00a0mg\/kg) and TAM (45\u00a0mg\/kg) orally for 10\u00a0days.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>TAM increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), triggered several histopathological alterations, NF-\u03baB p65, increased hepatic oxidative stress, and pro-inflammatory cytokines. PIO protects against TAM-induced liver dysfunction, reduced malondialdehyde (MDA), and pro-inflammatory markers along with improved hepatic antioxidants.\u00a0Moreover, PIO, increased hepatic Bcl-2 expression while reducing Bax expression and caspase-3 levels. In addition, PIO decreased Keap-1, Notch1, and Hes-1 while upregulated HO-1, Nrf2, and SIRT1. Molecular docking showed the binding affinity of PIO for Keap-1, NF-\u03baB, and SIRT1.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>PIO mitigated TAM hepatotoxicity by decreasing apoptosis, inflammation, and oxidative stress. The protecting ability of PIO was accompanied by reducing Keap-1 and NF-\u03baB and regulating Keap1\/Nrf2\/HO-1 and Sirt1\/Notch1 signaling.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Graphical abstract<\/jats:title>\n                <jats:p>A schematic diagram illustrating the protective effect of PIO against TAM hepatotoxicity. PIO prevented TAM-induced liver injury by regulating Nrf2\/HO-1 and SIRT1\/Notch1 signaling and mitigating oxidative stress, inflammation, and apoptosis.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s11033-023-08847-x","type":"journal-article","created":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T10:01:49Z","timestamp":1699351309000},"page":"10219-10233","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Pioglitazone attenuates tamoxifen-induced liver damage in rats via modulating Keap1\/Nrf2\/HO-1 and SIRT1\/Notch1 signaling pathways:\u00a0In-vivo investigations, and molecular docking analysis"],"prefix":"10.1007","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6980-4726","authenticated-orcid":false,"given":"Gellan Alaa Mohamed","family":"Kamel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0122-4968","authenticated-orcid":false,"given":"Hemat A.","family":"Elariny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,7]]},"reference":[{"key":"8847_CR1","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/j.jfma.2015.05.006","volume":"115","author":"HJ Pan","year":"2016","unstructured":"Pan HJ, Chang HT, Lee CH (2016) Association between tamoxifen treatment and the development of different stages of nonalcoholic fatty liver disease among breast cancer patients. 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