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This study aimed to investigate the inhibitory effects of two natural flavonoids, hesperetin (HT) and hesperidin (HD), on two gluconeogenesis enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and their possible mechanisms of action.Rat liver incubated with different concentrations of HT and HD was used to measure enzyme activities spectrophotometrically, based on monitoring the oxidation of NADH to NAD+ at 340 nm. Molecular docking simulation was also applied to reveal the molecular mechanism of the inhibition caused by HT and HD.Both flavonoids demonstrated inhibitory effects against the enzyme activities, with IC50 values of 153.9 and 68.88 μM for HT-ALT and HD-ALT treatment respectively. Likewise, the IC50 values of 85.29 μM for HT-AST and 110.3 μM for HD-AST were obtained from spectrophotometric results.The docking simulation revealed that HT and HD block the enzyme entrance channel and prevent the substrates from accessing the enzyme active sites. Having prevented production of pyruvate, α-ketoglutarate, and the oxaloacetate, these two compounds inhibit hepatic gluconeogenesis and consequently, hinder the progression of diabetes.This study suggests that HT and HD may be considered as leading compounds for designing safe and effective drugs in management of increased ALT and AST-related disorders specially diabetes.