Empagliflozin attenuates dexamethasone-induced non-alcoholic steatohepatitis by regulation of ferroptosis, inflammation and autophagy

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Purpose: rats. Methods: NASH was induced by daily injection of DEXA (8 mg/kg/day, i.p.) from day 8-13. EMPA (10 and 30 mg/kg) was administered orally for 13 days from day 1-13. on day 14, serum and liver tissue were obtained and assessed using biochemical and histological assessments. Results: EMPA (10 and 30 mg/kg) considerably ameliorated NASH brought on by DEXA. A marked decrease in serum levels of ALT and AST was observed upon EMPA treatment confirmed by histopathological analysis. EMPA significantly improved metabolic parameters, as evidenced by reductions in serum glucose and insulin levels and a marked improvement in HOMA-IR. EMPA significantly ameliorated dyslipidemia by reducing serum levels of TG, TC, LDL-C, VLDL-C, and FFA, while partially restoring serum HDL-C levels. Hepatic oxidative stress markers, MDA and 4-HNE were markedly reduced, whereas hepatic antioxidant defences, Nrf2, GSH and GPX4 were significantly enhanced. Furthermore, EMPA effectively restored iron homeostasis and alleviated signs of iron overload by down-regulating serum iron and upregulation of hepatic ferritin, transferrin, and hepcidin. EMPA treatment led to a marked decrease in hepatic calcium and calcineurin A levels, which was associated with modulation of autophagy, as evidenced by increased LC3-II and decreased p62 and Beclin-1 expression in the liver. EMPA downregulated pro-inflammatory and fibrotic biomarkers, NF-κB, IL-6, and TGF-β1, as well as markers for hepatic lipid accumulation, FABP1, PPAR-γ and CD36. It also significantly suppressed the hepatic gene and protein expression of NCOA4, the ferritinophagy biomarker, with enhanced FTH1 hepatic gene and protein expression. Conclusion: EMPA effectively ameliorated DEXA-induced NASH via reducing liver damage caused by excess iron by restoring the appropriate levels of iron, preventing ferroptosis, restoring lipid homeostasis, reducing oxidative stress, and managing inflammation and fibrosis.

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