Methotrexate (MTX) administration causes hepatotoxicity, a serious side effect limiting its clinical use. Therefore, this study was performed to investigate the beneficial effect of empagliflozin (Empa) against MTX-induced hepatotoxicity. Adult male albino mice were pre-treated with Empa (at 10 or 25 mg/kg/d, orally) for 6 days and then received a single MTX injection (at 20 mg/kg, intraperitoneally). Empa effectively ameliorated MTXinduced structural and functional alterations. It significantly decreased transaminase, alkaline phosphatase, and gamma-glutamyl transferase levels and increased albumin levels in the serum. Moreover, Empa restored the oxidant/antioxidant balance as indicated by reduced malondialdehyde and total nitrite/nitrate contents and elevated reduced glutathione level and superoxide dismutase activity. Additionally, Empa (10 and 25 mg/kg) markedly suppressed the elevated levels of tumor necrosis factor-alpha, interleukin-6, apoptosis signal-regulating kinase1, c-Jun N-terminal kinase, BCL2 associated X protein, and Caspase-3 in hepatic tissues and increased the hepatic interleukin-10 levels. Furthermore, Empa substantially decreased nuclear factor kappa B expression in hepatic tissues. These biochemical findings were further confirmed by histopathological and transmission electron microscopy observations. Therefore, Empa might be used as an adjuvant to ameliorate MTX-induced hepatotoxicity after further clinical evaluation.
