Assessment of Antihyperglycemic and Modulatory Effects of <i>trans</i> ‐Ferulic Acid on Glibenclamide and Metformin: In Vivo and Molecular Docking Studies

Abstract Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to impaired insulin secretion, insulin resistance, or both. trans ‐Ferulic acid (TFA) has several biological activities, including sedative, anxiolytic, anti‐inflammatory, and so on. However, there is no in vivo and in silico study on the antihyperglycemic activity of TFA. This study assessed the antidiabetic potential of TFA and its modulatory effect on glibenclamide (GLI) and metformin (MET) through in vivo hypoglycemic tests in mice and in silico molecular docking targeting glucose metabolism proteins. TFA (25, 50, and 75 mg/kg, p.o.) was tested in glucose‐induced hyperglycemic mice alongside GLI (10 mg/kg, p.o.) and MET (100 mg/kg, p.o.), with blood glucose levels (BGLs) monitored. TFA significantly ( p &lt; 0.05) reduced BGLs in a dose‐dependent manner, with the 75 mg/kg dose achieving a 30.99% reduction at 180 min, compared to 52.04% (GLI) and 55.27% (MET). Combination therapy (TFA‐50+GLI‐10 and TFA‐50+MET‐100) further enhanced glucose‐lowering effects, with TFA‐50+GLI‐10 showing the highest reduction (58.90%). In silico analysis revealed that TFA exhibited elevated binding affinities with complex I (−6.4 kcal/mol) and mitochondrial glycerol‐3‐phosphate dehydrogenase (−6.8 kcal/mol). These findings suggest TFA has significant hypoglycemic potential, supporting its role in glucose regulation.