Empagliflozin Inhibits Cadmium-Induced Hepatic Cell Apoptosis Through Endoplasmic Reticulum Stress and Autophagy Pathways

Cadmium (Cd), a well-known toxic heavy metal, adversely affects multiple organs. The SGLT-2 inhibitor empagliflozin (EMPA) exhibits significant antioxidant properties and hypoglycemic potential. This study aimed to investigate the hepatoprotective effect of EMPA against Cd-induced liver injury and elucidate its molecular mechanisms. Thirty-two male rats were allocated into four groups of eight rats each: group I (control group), group II (EMPA group), group III (Cd group), and group IV (Cd + EMPA group). Cd intake disrupted liver enzymes (ALT, AST, and ALP) and impaired hepatic histological architecture. Cd induced hepatic oxidative stress, as evidenced by increased MDA levels and reduced antioxidant enzymes, including SOD, GPx, and CAT. It downregulated the Nrf2/HO-1 pathway and elevated proinflammatory mediators IL-1 beta, IL-6, and TNF-alpha. Furthermore, Cd increased ER stress markers GRP78 and CHOP, along with apoptotic markers Bax and caspase-3 while decreasing anti-apoptotic Bcl-2 and reducing the autophagic indicator Beclin-1. Interestingly, EMPA administration in the Cd + EMPA group attenuated Cd-induced hepatic deterioration, improving hepatocyte structure. This beneficial effect was driven by the downregulation of hepatic oxidative stress, inflammation, ER stress, and apoptosis, alongside the upregulation of the autophagy process. In conclusion, this study highlights the hepatoprotective effect of EMPA against Cd-induced liver injury, elucidating its underlying molecular mechanisms.