Novel mechanisms through which chronic hypoxia activates HIF-2α, affecting glutamine catabolism in HSC-derived myofibroblasts, that were found in this study include: (1) Direct enhancement of fibrosis by HIF-2α in NASH through increased glutaminolysis; (2) Inhibition of mitochondrial activity in hepatocytes (but enhancement in HSCs) by HIF-2α; (3) Increase in GLS1 expression in HSCs by HIF-2α, mediated through YAP; and (4) Inhibition of p-YAP but enhancement of YAP by HIF-2α, facilitating YAP nuclear transfer, interaction with TAZ, and GLS1 mRNA expression. Here, EPAS1 is linked to metabolic dysfunction-associated steatohepatitis.