Our data lead us to propose a working model for the role of CHOP in HCC (Figure 7): Hepatocyte injury, be it in the form of lipotoxicity associated with obesity, the toxicity of ethanol metabolism, viral hepatitis, or genotoxic challenge, leads to activation of the ISR and production of CHOP either directly or after the initial formation of preneoplastic lesions such as the foci of cellular alteration that constitute some of the nodules produced by DEN. The gene discussed is DDIT3; the disease is obesity due to melanocortin 4 receptor deficiency.