Figure 2.

(A) In the course of NASH progression, chronic inflammation is induced by oxidative stress in which reactive oxygen species (ROS), lipotoxicity exacerbated by ROS, pathogen-associated molecular patterns (PAMP), and damage-associated molecular patterns (DAMP) such as lipopolysaccharides, adipokines, and insulin resistance promote fibrosis progression to cirrhosis, with shifting of hepatocytic Smad3 phospho-isoform signaling from tumor suppression to carcinogenesis, increasing risk of HCC. ECM, extracellular matrix. (B) Even in the absence of chronic inflammation and progressive fibrosis, an inflammation-independent process of hepatic carcinogenesis may occur as a result of genetic or epigenetic alteration. In such situations, direct DNA damage may occur from insulin resistance and lipotoxicity, as well as ROS caused by oxidative stress. Thus, mutations in key pathway components lead to sustained linker phosphorylation of Smad3, impairing sensitivity to growth inhibition by pSmad3C.