Protective effects of dapagliflozin against methotrexate-induced liver injury: Involvement of Nrf2/HO-1 and NLRP3 inflammasome.
TL;DR
It is suggested that Dap protects against MTX-induced liver injury by modulating antioxidant defenses and inflammatory signaling pathways by modulating antioxidant defenses and inflammatory signaling pathways.
Abstract
Methotrexate (MTX) is a chemotherapeutic and immunosuppressive agent that can induce liver injury through oxidative stress and inflammatory mechanisms. Dapagliflozin (Dap), a selective SGLT2 inhibitor, exerts antioxidant and anti-inflammatory effects. This study investigated the protective effects of Dap against MTX-induced liver injury, with a focus on oxidative stress, Nrf2/HO-1 signaling, and NLRP3-related inflammatory responses. Twenty-four male albino rats were divided into four groups: control, MTX (20 mg/kg, single i.p. dose), MTX + Dap 5 mg/kg, and MTX + Dap 10 mg/kg, with Dap administered orally once daily for 10 days. MTX increased serum ALT and AST levels, elevated hepatic MDA, reduced GSH and SOD levels, and induced histopathological alterations. In addition, MTX decreased Nrf2 mRNA and HO-1 protein expression, while increasing NLRP3 mRNA, TNF-α, and IL-1β levels. Dap treatment improved liver enzyme profiles and histopathological features, enhanced antioxidant markers, upregulated Nrf2 mRNA and HO-1 protein expression, and downregulated NLRP3 mRNA and pro-inflammatory cytokine levels in a dose-dependent manner. Correlation analysis indicated that higher Nrf2 levels were associated with reduced oxidative stress and NLRP3-related gene expression. These findings suggest that Dap protects against MTX-induced liver injury by modulating antioxidant defenses and inflammatory signaling pathways.