Dapagliflozin attenuates methotrexate-induced hepatorenal toxicity in rats: insights into oxidative stress, inflammation, autophagy and apoptosis.

Methotrexate (MTX) is a potent chemotherapeutic drug used to treat various malignancies, and serious autoimmune diseases. Unfortunately, the potential liver and kidney toxicities of MTX restrict its clinical effectiveness. The present study aims to explore the protective effects of dapagliflozin (Dapa) against MTX-induced hepatorenal toxicity in a rat model. Eighteen male Sprague-Dawley rats were randomly distributed into three groups; Normal, MTX and MTX + Dapa, rats received Dapa (10 mg/kg) orally once daily for 10 days; and a single i.p. injection of MTX (20 mg/kg) on the fifth day. The Dapa ameliorated hepatorenal histopathological changes induced by MTX and modulated liver and kidney function biomarkers. Dapa significantly upregulated the expression of PPAR-γ /Nrf-2/HO-1 which in turn downregulated the expression of NF-κB in hepatic and renal sections. Also, Dapa restored hepatic and renal tissues oxidative balance via significant elevation of GSH content and lowering MDA content. Moreover, Dapa modulated beclin1/LC3 dependent autophagy and caspase-3/Bcl-2 mediated apoptosis in hepatic and renal tissues. In conclusion, Dapa showed substantial hepatorenal protection against MTX-induced hepatorenal toxicity, highlighting a new therapeutic strategy in MTX treatment protocols.