Fig. 6. A schematic model.

In the DEN-induced HCC model, DEN induces hepatocyte death. The dying cells release IL1α, which activates Kupffer cells. Activated Kupffer cells produce TNFα, which induces hepatocyte death and promotes expansion of the hepatocytes carrying DNA mutations, thus enhancing HCC development. p38 hyperactivation promotes TNFα-mediated hepatocyte death. Caspase-3 suppresses p38 activation in hepatocytes thereby Caspase-3 deletion increases the activation of p38 and enhances hepatocyte death, the subsequent compensatory proliferation and the development of HCC, all induced by DEN.