Empagliflozin attenuates cyclophosphamide-induced hepatotoxicity via targeting Nrf2/HO-1 signaling, oxidative stress, and inflammation

Abstract

Cyclophosphamide (CYP) is the most commonly used antineoplastic against numerous malignant tumors. Hepatic injury induced by CYP is a pivotal issue in clinical practice that limits its therapeutic use. In this study, CYP induced significant hepatotoxicity that is manifested by functional, biochemical, and histopathological alterations.This was linked with a significant increase of hepatic oxidative/nitrosative stress along with elevated hepatic contents of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), which seems to be among the key biomarkers that modulate the hepatotoxicity of CYP. Besides, inflammatory biomarkers; of tumor necrosis factor-α (TNF-α) and nuclear factor kappa B (NF-κB); significantly increased with significant multiple individual cell deaths and vacuolar degeneration in hepatocytes. Empagliflozin (EMP); a potent and selective SGLT2 inhibitor; possesses anti-inflammatory, anti-fibrotic, and antioxidant effects. EMP's co-administration with CYP in the current study induced a significant restoration of hepatocyte architecture which appears to be primarily mediated via modulation of Nrf2/HO-1 signaling and in turn attenuation of CYP-induced oxidative stress and inflammatory responses. In conclusion; EMP attenuated CYP-induced hepatotoxicity by modulation of Nrf2/HO-1 signaling pathway and consequent inhibition of oxidative stress and inflammation.