Dapagliflozin Alleviates Non-Alcoholic Fatty Liver Disease in Mice by Inhibiting Ferroptosis through Activating the SIRT1/Nrf2 Pathway

Ferroptosis, an iron-dependent cell death form, has been identified to be closely related to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Dapagliflozin (DAPA), as the most representative drug of sodium-glucose cotransporter 2 (SGLT2) inhibitors, shows potential benefits for NAFLD prevention and treatment. However, it remains unknown whether and how DAPA alleviates hepatic ferroptosis in NAFLD. Here our research used high-fat diet (HFD) feeding to establish NAFLD mouse models and treated HepG2 cells with free fatty acid (FFA) mixture (oleic acid and palmitic acid) to construct fatty hepatic steatosis cellular models. We discovered that DAPA administration ameliorated global metabolic abnormalities, attenuated liver lipid deposition, and impeded disease progression in NAFLD mice. DAPA treatment markedly improved HFD-induced hepatic lipid peroxidation and ferroptosis. The inhibitory effects of DAPA on hepatocyte ferroptosis and lipid accumulation were also observed in FFA-treated HepG2 cells. Mechanistically, DAPA treatment promoted the SIRT1/Nrf2 signaling pathway. The SIRT1 inhibitor EX527 overturned the anti-lipid deposition and anti-ferroptotic effects of DAPA in FFA-treated HepG2 cells. Collectively, DAPA suppresses hepatic ferroptosis in NAFLD by activating the SIRT1/Nrf2 pathway, proving that targeting DAPA-mediated ferroptosis is a promising therapeutic method for treating NAFLD.