Mechanistic evidence for PI3K/Akt-driven reactivation of Nrf2/HO-1 by dapagliflozin in acute cisplatin hepatotoxicity

Abstract

BACKGROUND: While nephrotoxicity remains the most recognized adverse effect of cisplatin, hepatotoxicity is increasingly acknowledged as a significant clinical concern. OBJECTIVE: This study evaluated the hepatoprotective effect of dapagliflozin (DAPA), a selective sodium-glucose cotransporter-2 inhibitor, focusing on its modulation of the PI3K/Akt-Nrf2/HO-1 signaling pathway. METHODS: Male Wistar albino rats received oral dapagliflozin (5 or 10 mg/kg/day) for 14 days, with a single intraperitoneal injection of cisplatin (7.5 mg/kg) administered on Day 7. Biochemical, molecular, and histopathological assessments were conducted. RESULTS: Cisplatin induced marked hepatic injury, evidenced by body weight loss, hepatomegaly, hyperglycemia, impaired liver function, oxidative stress, inflammation, and apoptosis dysregulation. Dapagliflozin pretreatment significantly and dose-dependently mitigated these effects. It reduced lipid peroxidation and nitric oxide levels while enhancing antioxidant defenses, including Nrf2, heme oxygenase-1, and superoxide dismutase. Additionally, dapagliflozin restored PI3K/Akt signaling, suppressed NF-κB-mediated inflammatory responses, and normalized apoptotic balance. Histological findings corroborated biochemical results, showing preservation of hepatic architecture, particularly at the higher dose. CONCLUSIONS: Dapagliflozin exerts significant hepatoprotective effects against cisplatin-induced toxicity via antioxidant, anti-inflammatory, and cytoprotective mechanisms, supporting its potential as an adjunct to improve cisplatin safety.