It illustrates how (i) dyslipidaemia-induced NOX4 activation, combined with LKB1/AMPK suppression, impairs metabolic homeostasis; (ii) aldehydic “second hits” such as 4-HNE, acrolein, MGO/GO, and 3-DG exacerbate NOX–iNOS crosstalk via peroxynitrite formation; and (iii) progressive exhaustion of G6PD/NADK and LKB1/AMPK ultimately drives a fibro-sclerotic transition that feeds forward into endothelial dysfunction and neuroinflammation along the liver. The gene discussed is NOS2; the disease is endothelial dysfunction.