Increase in FFA, TNF-α, and ROS levels (as observed during the onset and progression of NAFLD) are potent activators of JNK1 and are all found elevated/activated upon the development of murine and human HCC.19, 20, 40 Moreover, the activity of STAT3 that is frequently activated in human HCC and implicated in the development of chemically and obesity-induced HCC,15, 20, 44 was significantly enhanced in DKO tumors. This evidence concerns the gene MAPK8 and obesity due to melanocortin 4 receptor deficiency.