Therapeutic efficacy of canagliflozin against hepatocarcinogenesis induced by CDD/DEN/TAA in a rat model: regulation of AMPK/HIF-1α/YAP-1/TAZ signaling pathways

Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer. Many medications that had been used for a long period to treat the illness were eventually stopped due to negative effects or the development of drug resistance in HCC patients. Canagliflozin (CANA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, showed in vitro anti-carcinogenic efficacy against various cancer models' other livers. The current study used rat models to examine canagliflozin's therapeutic role against experimentally induced HCC. A total of 32 rats were divided into four groups, eight in each: negative control; HCC control: rats were fed a choline-deficient diet (CDD) and subjected to diethyl nitrosamine and thioacetamide (DEN/TAA) injections for 15 weeks; and treated groups: rats were given CANA (10 and 20 mg/kg b.wt.) orally from the 7th week of the experiment till the end. All the measured markers of HCC, liver function, and inflammatory markers were elevated in the HCC control group compared to the negative control (CTRL). Regarding immunohistochemistry, the HCC group showed downregulation in caspase-3 expression and upregulation in PCNA expression. On the other hand, canagliflozin-treated groups showed dose-dependent improvement in the measured parameters associated with HCC. Moreover, canagliflozin therapy ameliorates the histopathological alterations in HCC-induced rats. Taken together, CANA exhibits anti-HCC effects by activating AMP-activated protein kinase (AMPK) and suppressing the HIF-1α/YAP/TAZ pathway, making it a forthcoming therapeutic option for HCC.