Several experimental and clinical studies strongly suggest that acute APAP hepatotoxicity could be more frequent and more severe in obesity and NAFLD [8,49,50,54]. This is probably because these diseases are often associated with higher hepatic CYP2E1 activity, which generates greater levels of the toxic NAPQI metabolite. However, some obese individuals do not present high CYP2E1 activity and thus they may not be at risk for APAP-induced liver injury. Here, CYP2E1 is linked to metabolic dysfunction-associated steatotic liver disease.