IntroductionThe 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.MethodsA 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.ResultsComputational 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’s ability to directly inhibit PTP1B activity. Animal experiments demonstrated ondansetron’s 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’s anti-inflammatory and antioxidant activities were evident in its ability to reduce pro-inflammatory markers and oxidative stress in the liver.DiscussionThese 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.