In this study, using PF-429242, an active-site-directed inhibitor of SKI-1/S1P, we demonstrated that strategic manipulation of human SKI-1/S1P enzymatic activity in Huh-7.5.1 human hepatoma cells provides a means of interfering with the SKI-1/S1P-mediated proteolytic activation of the SREBP pathway. The gene discussed is MBTPS1; the disease is hepatocellular carcinoma.