The role of the Microbiome in NAFLD and HCC Jun Yu Professor, Department of Medicine and Therapeutics, The Chinese University of Hong Kong Non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is an emerging malignancy worldwide. However, the molecular mechanism of NAFLD-HCC is largely unknown, and targeted therapy is currently not available (Yu J et al, Semin Cancer Biol 2013). We identified the link of cholesterol to NASH and NASH-HCC and provide potential therapeutic targets (Yu J et al. Nature Commun 2018). Moreover, SQLE, the rate-limiting enzyme in cholesterol biosynthesis, is highly expressed in human NAFLD-HCCs. Hepatocyte-specific Sqle transgenic mice accelerated the development of HFHC-HCC and is a therapeutic target (Yu J et al. Sci Transl Med 2018). Dietary cholesterol induced gut bacterial metabolites alteration including increased Taurocholic acid and decreased 3-Indolepropionic acid. Germ-free mice gavaged with stools from mice fed HFHC manifested hepatic lipid accumulation, inflammation, immunity change and cell proliferation. Moreover, Atorvastatin (cholesterol inhibitor) restored cholesterol-induced gut microbiota dysbiosis and metabolomics changes, which completely prevented NAFLD-HCC development (Yu J et al. Gut 2020). Collectively, cholesterol drives NAFLD-HCC formation by inducing alteration of gut microbiota, metabolites and host immunity in mice. Cholesterol inhibitory therapy and gut microbiota manipulation may be effective strategies for NAFLD-HCC prevention.