ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevation of GPX4 expression and lipid accumulation

Background:ENO3 expression is upregulated in Non-alcoholic fatty liver disease (NAFLD) patient tissues, demonstrated that ENO3 might play crucial roles in NAFLD. However, the mechanism of ENO3 in NAFLD remains unclear. Therefore, this study aimed to investigate the regulatory mechanism of ENO3 in the progression of non-alcoholic steatohepatitis (NASH) in vivo and vitro NASH model.

Methods:In vivo and vitro NASH model were established by methionine-choline deficient (MCD)-diet feeding and high free fatty acid (HFFA) induction in L02 cells. Loss and gain function of ENO3 and GPX4 was performed to study the mechanism in NASH. Western blot was used to detect the expression of ENO3 and GPX4. Hematoxylin and eosin (H&E), picrosirius Red and Oil Red O staining was used to evaluate histopathology of liver in NASH model. Ferroptosis indicators were measured by assay kits according to the manufacturer's instructions.

Results:NASH mouse model was successfully established induced by MCD diet with steatosis, inflammatory infiltration, ballooning and fibrosis observed in the liver tissue. The expression of ENO3 and GPX4 was significantly elevated while ferroptosis was inhibited in NASH mice and cell model. Upregulation of both ENO3 and GPX4 could promote the lipid accumulation in L02 cells. In addition, overexpressed ENO3 attenuated the status of ferroptosis.

Conclusions:In the present study, we demonstrate that ENO3 promoted the progression of NASH by negatively regulating ferroptosis via elevating GPX4 expression and lipid accumulation. These findings provided solid foundation for the mechanism of ferroptosis on the progression of NASH regulated by ENO3, suggesting that ENO3 may be a potential therapeutic target for NASH.

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