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Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The escalating prevalence of diabetes and non-alcoholic fatty liver disease (NAFLD) has intensified the search for effective therapeutic interventions. The current study investigates the potential of ondansetron, a Food and Drug Administration (FDA)-approved drug for conditions like nausea and vomiting, as a novel treatment option for these metabolic disorders.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A multifaceted approach, encompassing computational analyses, in vitro enzyme inhibition assays, and in vivo experiments in a high-fat diet (HFD)-induced disease model in rats were employed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Computational studies, including pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulations, revealed the strong binding affinity of ondansetron to the allosteric site of protein tyrosine phosphatase 1B (PTP1B), a key regulator of insulin and lipid homeostasis. The in vitro enzyme inhibition assay further confirmed ondansetron\u2019s ability to directly inhibit PTP1B activity. Animal experiments demonstrated ondansetron\u2019s antihyperglycemic effects, reducing blood glucose levels and improving insulin sensitivity in HFD-fed rats. The drug also exhibited hepatoprotective properties, mitigating liver damage and improving tissue architecture. Additionally, ondansetron\u2019s anti-inflammatory and antioxidant activities were evident in its ability to reduce pro-inflammatory markers and oxidative stress in the liver.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These therapeutic effects position ondansetron as a promising candidate for further investigation in clinical settings for the treatment of diabetes and NAFLD and, hence, support the use of the drug repurposing approach for addressing the growing burden of metabolic diseases.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1565628","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T05:30:39Z","timestamp":1745818239000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The effects of ondansetron on diabetes and high-fat diet-induced liver disease: a critical role for protein tyrosine phosphatase 1B"],"prefix":"10.3389","volume":"16","author":[{"given":"Fawad","family":"Naeem","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maryam","family":"Aqeel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Muhammad Ammar","family":"Zahid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mustafeez Mujtaba","family":"Babar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fawad Ali","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdelali","family":"Agouni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sohaib Zafar","family":"Malik","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"665","DOI":"10.3892\/mmr.2021.12304","article-title":"Protein tyrosine phosphatase 1B inhibition improves endoplasmic reticulum stress-impaired endothelial cell angiogenic response: a critical role for cell survival","volume":"24","author":"Abdelsalam","year":"2021","journal-title":"Mol. 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