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FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP\u20104 inhibitor known for its safe profile, has exhibited noteworthy anti\u2010inflammatory and anti\u2010oxidative properties in previous in\u00a0vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10\u2010week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NF\u03baB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti\u2010inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK\/FOXO3a signaling pathway in the management of chronic liver damage.<\/jats:p>","DOI":"10.1096\/fj.202302461rr","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T11:44:40Z","timestamp":1707911080000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Linagliptin, a\n                    <scp>DPP<\/scp>\n                    \u20104 inhibitor, activates\n                    <scp>AMPK<\/scp>\n                    \/\n                    <scp>FOXO3a<\/scp>\n                    and suppresses\n                    <scp>NF\u03baB<\/scp>\n                    to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights"],"prefix":"10.1096","volume":"38","author":[{"given":"Rasha","family":"Abdelhady","sequence":"first","affiliation":[{"name":"Pharmacology and Toxicology Department, Faculty of Pharmacy Fayoum University  Fayoum Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osama A.","family":"Mohammed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, College of Medicine University of Bisha  Bisha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0136-7096","authenticated-orcid":false,"given":"Ahmed S.","family":"Doghish","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Pharmacy Badr University in Cairo (BUC)  Badr City Egypt"},{"name":"Department of Biochemistry and Molecular Biology, Faculty of Pharmacy Al\u2010Azhar University  Nasr City Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabab S.","family":"Hamad","sequence":"additional","affiliation":[{"name":"Biological Sciences Department, College of Science King Faisal University  Al Ahsa Saudi Arabia"},{"name":"Central Laboratory Theodor Bilharz Research Institute  Giza Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa Ahmed","family":"Abdel\u2010Reheim","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy Shaqra University  Aldawadmi Saudi Arabia"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy Beni\u2010Suef University  Beni Suef Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohannad Mohammad S.","family":"Alamri","sequence":"additional","affiliation":[{"name":"Department of Family and Community Medicine, College of Medicine University of Bisha  Bisha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muffarah Hamid","family":"Alharthi","sequence":"additional","affiliation":[{"name":"Department of Family and Community Medicine, College of Medicine University of Bisha  Bisha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaber","family":"Alfaifi","sequence":"additional","affiliation":[{"name":"Department of Child Health, College of Medicine University of Bisha  Bisha Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masoud I. 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