Empagliflozin Alleviates Hepatic Steatosis and Oxidative Stress via the NRF1 Pathway in High-Fat Diet-Induced Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease

Empagliflozin (EMPA)-a sodium-glucose cotransporter type 2 inhibitor-reduces endoplasmic reticulum (ER) stress, oxidative stress, and inflammation during metabolic dysfunction-associated steatotic liver disease (MASLD) progression. However, the direct effects of EMPA on hepatic lipid metabolism and oxidative stress are unclear. Through the current study, we seek to explore the effects of EMPA on oxidative stress and related mechanisms in MASLD. To this end, MASLD was induced in C57BL/6J mice using a high-fat diet (HFD); nuclear respiratory factor 1 (NRF1) was downregulated via viral transduction (AAV8-shNrf1). Glucose homeostasis and liver histology were assessed, and oxidative stress and inflammation were measured. HFD-fed mice-derived liver tissue samples exhibited more lipid droplets, higher triglyceride levels, and elevated oxidative and ER stress than chow diet (CD)-fed mice. EMPA attenuated HFD-induced liver oxidative and ER stress. Additionally, the HFD significantly decreased NRF1 and Sirtuin (SIRT)7 expression compared with CD, which was rescued by EMPA treatment. However, these results did not affect insulin resistance or lipid synthesis-related changes upon EMPA treatment in the <i>Nrf1</i>-knockdown mice. Furthermore, EMPA alleviated HFD-induced hepatic steatosis and oxidative stress; however, these effects were lost in <i>Nrf1</i>-knockdown mice. Collectively, the results of this study suggest that EMPA ameliorates MASLD by reducing steatosis and attenuating oxidative stress via NRF1.