Empagliflozin mitigates doxorubicin-induced hepatotoxicity by reducing inflammation, oxidative stress, and apoptosis in male NMRI mice.

Doxorubicin (DOX) is an effective chemotherapeutic agent widely used against various malignancies; however, its clinical utility is limited by dose-dependent hepatotoxicity. Empagliflozin (EMPA), a sodium-glucose co-transporter-2 (SGLT2) inhibitor, has demonstrated antioxidant, anti-inflammatory, and anti-apoptotic properties. This study aimed to evaluate the protective effects of EMPA against DOX-induced liver injury. Twenty-eight adult male Naval Medical Research Institute (NMRI) (8–12 weeks old) mice were randomly divided into four groups (n = 7 per group): the DOX group received 2 mg/kg intraperitoneally on days 1, 7, 14, 21, and 28. DOX + EMPA group, in addition to receiving a 2 mg/kg intraperitoneally on days 1, 7, 14, 21 and 28 of doxorubicin, at the same time received 10 mg/kg/day intraperitoneally empagliflozin for 28 days, the EMPA group received 10 mg/kg/day intraperitoneally empagliflozin for 28 days, and the control group did not receive any medications. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), Gamma-glutamyl transferase (GGT), and total bilirubin, interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), malondialdehyde (MDA), and ferric reducing antioxidant power (FRAP) were assessed. Liver histology was examined using H&E and Periodic Acid-Schiff (PAS) staining, and hepatocyte apoptosis was quantified via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Co-administration of EMPA attenuated DOX-induced elevations in ALT (1.5 fold), AST (1.4 fold), ALP (1.4 fold), GGT (1.7 fold), total bilirubin (1.6 fold), IL-6 (1.8 fold), TNF-α (1.7 fold), and MDA (1.7 fold) levels, while enhancing FRAP (2.4 fold) levels. Histological evaluation revealed improved hepatic architecture and reduced hepatocyte apoptosis in the DOX + EMPA group compared to the DOX group. Empagliflozin confers hepatoprotective effects against doxorubicin-induced toxicity by modulating oxidative stress, inflammatory cytokines, and apoptotic activity. These findings suggest potential therapeutic benefits of EMPA as an adjuvant in chemotherapy-induced liver injury.