Approximately 240 and 71 million people suffer from chronic HBV and chronic HCV infection, respectively. Chronic HBV and HCV infections represent the leading cause for hepatocellular carcinoma. Hepatocellular carcinoma carries high economic burden on society. Owing to the high risk of developing end-stage liver disease or hepatocellular carcinoma, CHB is associated with high mortality, with 880,000 deaths per year. Similarly, 500,000 people die each year from chronic HCV-related liver diseases such as liver cirrhosis or hepatocellular carcinoma. HBV initiates the neoplastic process while HCV acts as a promoter having a synergistic effect in causing hepatocellular carcinoma. The risk for hepatocellular carcinoma in chronic HBV and HCV infection is linked to liver inflammation that drives fibrosis, cirrhosis and hepatocellular carcinoma. It is the persistent inflammation and destruction of hepatocytes that leads to carcinogenesis. The risk of hepatocellular carcinoma development remains after virus elimination, especially for patients who had advanced liver cirrhosis at the time of treatment. More than 100 trials evaluating chemotherapy or targeted therapies in hepatocellular carcinoma failed to show survival advantage. Thus, it is of the utmost importance to identify novel therapeutic approaches to treat viral hepatitis-induced hepatocellular carcinoma.

Recent results from the lab: Recently our lab identified a novel class of compounds called cyclophilin inhibitors including CRV431, NV556 and Alisporivir, which possess dual therapeutic activities critical for preventing the development of viral hepatitis-induced hepatocellular carcinoma. We very recently published that cyclophilin inhibitors not only inhibit HCV and HBV replication in vitro and in vivo, but also discovered that they inhibit the development of hepatocellular carcinoma by inhibiting the development of the early steps of hepatocellular carcinoma – non-alcoholic steatohepatitis and liver fibrosis – in several mouse models that we developed in the lab.

Cyclophilin inhibitors neutralize the enzymatic activity of cyclophilins, which regulate multiple cellular functions. An excellent review from Ure et al. describes in detail the plausible cellular functions of cyclophilin members that may lead to the development of non-alcoholic steatohepatitis, liver fibrosis and hepatocellular carcinoma (Ure et al. Expert Opinion on Investigational Drugs, 29:2, 163-178, DOI: 10.1080/13543784.2020.1703948).

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