Chronic hepatitis B and C and their subsequent liver fibrosis progression, cirrhosis, hepatocellular carcinoma (HCC) and death are important health challenges not only in Taiwan but also in other parts of the world. Long-term hepatic necroinflammation is the key to both fibrogenesis and carcinogenesis of liver. Although there is no effective anti-fibrotic agent available; currently, growing lines of evidence show successful anti-viral therapy may halt or reverse liver fibrosis, especially in the early stage. It is generally believed that chronic hepatitis, fibrosis, cirrhosis and HCC are consecutive processes, thus effective treatment at the earlier fibrosis stage should benefit clinical outcome most. However, existing data suggest that anti-viral therapy seems to reduce the development of HCC in cirrhotic patients only, but not in non-cirrhotic ones, probably due to the suboptimal follow-up period. On the other hand, even after anti-viral therapy, a significant proportion (~50%) of cirrhosis patients still develop HCC, implicating cirrhosis itself may be a point of no return in hepatocarcinogenesis. Taking these data together, little is known about the best timing for anti-viral therapy in patients with fibrosis and this important issue deserves further clinical as well as basic studies. To this end, we plan to retrospectively construct a HBV and HCV-related liver fibrosis cohort with long-term follow-up at the National Taiwan University Hospital to explore the clinical outcomes (cirrhosis and complications, HCC and death) of anti-viral treatment in these patients stratified by baseline liver histology and compared to those without treatment. Baseline serological, virological, and clinical parameters (including comorbidities such as diabetes mellitus, hyperlipidemia and medication history including HMG-CoA reductase inhibitors, angiotensin converting enzyme inhibitors, angiotensin- II receptor blocker and pioglitazone) will be collected for long-term clinical outcome prediction. In addition, we will prospectively follow patients receiving anti-viral therapy to investigate the regression of liver fibrosis by using serial non-invasive tests (eg. Fibroscan). Our recent data showed that the signal transducer and activator of transcription 3 (STAT3) pathway plays a critical role in hepatocarcinogenesis, and serves as the target of sorafenib and its derivative (SC-1). In our pilot study, we found the expression of phospho-STAT3 increased among hepatic stellate cells as fibrosis progressed in chronic hepatitis B patients receiving liver biopsy. We thus hypothesize that STAT3 pathway is a key factor in the fibrogenesis of hepatic stellate cells. In this proposal, we will investigate the anti-fibrotic activity of sorafenib and SC-1 in animal and culture system to explore the STAT3 pathway as a novel target of anti-fibrotic therapy and also to search for the best timing of anti-fibrotic therapy in the meantime.