Non-alcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases. Chronic hypoxia is related to the pathogenesis of NASH. HIF-2 alpha is the key gene for lipid metabolism, fibrosis, and inflammation in many cells. To identify the molecular mechanism through which hypoxia exposure increases the morbidity of NASH, the expression level of HIF-2 alpha was analysed and was found to be upregulated in human NASH liver. By constructing the NASH model of chronic hypoxia, the mice were housed at an altitude of 4300 m for 4 and 8 weeks, compared to the control groups that were housed at an altitude of 50 m. Histological studies showed that exposure to hypoxia promoted the activation of NF-kappa B by upregulating the expression of HIF-2 alpha, as well as that of the genes related to inflammation and fibrosis, thereby promoting the development of NASH both in vivo and in vitro. In summary, hypoxia-exposure could upregulate HIF-2 alpha to aggravate tissue fibrosis and inflammation by upregulating inflammation-related genes and fibrosis-related genes metabolites via the activated NF-kappa B pathway in NASH. Our results suggest that for NASH patients living at high altitudes, drug therapy could focus on treating tissue fibrosis and inflammation, and thus provides a new strategy for NASH treatment. (C) 2021 Elsevier Inc. All rights reserved.