The risk of hepatocellular carcinoma(HCC) development increases as hepatitis virus C(HCV)-related liver diseases progress,especially in patients with active inflammation.Insight into hepatic carcinogenesis have emerged from recent detailed analyses of transforming growth factor-β and c-Jun-N-terminal kinase signaling processes directed by multiple phosphorylated(phospho)-isoforms of a Smad3 mediator.In the course of HCV-related chronic liver diseases,chronic inflammation and host genetic/epigenetic alterations additively shift the hepatocytic Smad3 phospho-isoform signaling from tumor suppression to carcinogenesis,increasing the risk of HCC.Chronic inflammation represents an early carcinogenic step that provides a nonmutagenic tumor-promoting stimulus.After undergoing successful antiviral therapy,patients with chronic hepatitis C could experience a lower risk of HCC as Smad3 phospho-isoform signaling reverses from potential carcinogenesis to tumor suppression.Even after HCV clearance,however,patients with cirrhosis could still develop HCC because of sustained,intense carcinogenic Smad3 phospho-isoform signaling that is possibly caused by genetic or epigenetic alterations.Smad3 phospho-isoforms should assist with evaluating the effectiveness of interventions aimed at reducing human HCC. The risk of hepatocellular carcinoma (HCC) development increases as hepatitis virus C (HCV) -latedlated liver diseases progress, especially in patients with active inflammation. Insight into hepatic carcinogenesis have emergencies from recent detailed analysis of transforming growth factor-beta and c-Jun -N-terminal kinase signaling processes directed by multiple phosphorylated (phospho) -isoforms of a Smad3 mediator. In the course of HCV-related chronic liver diseases, chronic inflammation and host genetic / epigenetic alterations additively shift the hepatocytic Smad3 phospho-isoform signaling from tumor suppression to carcinogenesis, increasing the risk of HCC. Chronic inflammation represents an early carcinogenic step that provides a nonmutagenic tumor-promoting stimulus. After undergoing successful antiviral therapy, patients with chronic hepatitis C could experience a lower risk of HCC as Smad3 phospho-isoform signaling reverses from potential carcinogenesis to tumor suppression. Even after HCV clearance, However, patients with cirrhosis could still develop HCC because of sustained, intense carcinogenic Smad3 phospho-isoform signaling that is caused by genetic or epigenetic alterations. Smad 3 phospho-isoforms should assist with evaluating the effectiveness of interventions aimed at reducing human HCC.