We show that the induction and activation of NFE2L2 was reliant on ROS generated by both mitochondria and NOX4 and that Nox4 deletion in hepatocytes was sufficient to abrogate the antioxidant defense response to promote oxidative lipid and protein damage, cell death, inflammation and the transition to NASH and fibrosis in obesity. Here, NFE2L2 is linked to obesity due to melanocortin 4 receptor deficiency.