Molecular pathogenesis and new treatment strategies of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the 2nd major cause of cancer death and the only cancer type to continuously show increased incidence and mortality. The well-known risk factors for HCC are hepatitis B and C virus infection and unhealthy alcohol use.

Recently, nonalcoholic steatohepatitis (NASH), characterized by hepatic lipid infiltration, inflammation and fibrosis, has been identified as a new and rapidly growing underlying etiology of HCC.

Notably, the molecular mechanisms governing the transition from NASH to HCC remain elusive, which hampers the development of novel anti-HCC therapies.Our recent studies have identified STE20-type kinase STK25 as an intrahepatocellular lipid droplet-coating protein that critically controls liver lipid storage, inflammation, oxidative stress, and NASH development.

Based on these findings, we now hypothesize that STK25 is also an important mediator that triggers the initiation and progression of NASH-related HCC and a potential target for anti-HCC therapy.

The aim of this project is to elucidate molecular mechanisms linking NASH to HCC, with the focus on novel regulator STK25.

By combining analyses in patient cohorts and xenograft mouse model with in vitro assays, the project will contribute to our understanding of the complex and integrated processes that control the molecular pathogenesis of NASH-related HCC.

The project is also anticipated to lay the basis for first-in-category treatment of HCC based on pharmacological STK25 inhibitors.