Nonalcoholic fatty liver disease (NAFLD) is the liver component of the metabolic syndrome and reaches global epidemic proportions. Isolated steatosis is the most common form, but some patients progress towards nonalcoholic steatohepatitis (NASH). The latter predisposes to fibrosis, cirrhosis and cardiovascular disease. Determinants of progression towards NASH are unclear. In isolated steatosis, we have previously shown the presence of increased hepatic vascular resistance which potentially leads to low-flow ischemia and hepatic parenchymal hypoxia, triggering the transition to steatohepatitis. We hypothesize that this chronic hepatic hypoxia induces a specific subtype of cell death in steatotic hepatocytes, i.e. ferroptosis. This recently described cell death is mediated by iron-catalyzed membrane lipid peroxides and has been suggested to play an important role in NAFLD. We will study the presence of hepatic ferroptosis in relation to disease severity in a large human NAFLD cohort. The potential of hypoxia to induce ferroptosis will be assessed in an in vitro NAFLD model to study the trigger of ferroptosis. Furthermore, we will objectify the presence of hepatic parenchymal hypoxia and ferroptosis in a murine dietary model of NAFLD. Afterwards, we will test the potential of vasodilatory compounds (which reduce hepatic hypoxia) and a novel third-generation ferroptosis inhibitor to inhibit progression towards NASH and treat an established NASH in the murine dietary model.