Non-alcoholic steatohepatitis (NASH), a potential precursor of hepatocellular carcinoma (HCC), currently has no FDA-approved treatment. Recently, the known beneficial effects of fibroblast growth factor (FGF)19 and FGF21 on metabolism suggest that endocrine FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. Pharmacological application of endocrine FGF variants holds great promise as an effective therapeutic means for treating obesity, diabetes and NASH. The Pegylated FGF21 (MS-986036) and FGF19 agonist (NGM282) have been studied in clinical phase II trials. Our preliminary studies show that the lack of FGF21 accelerates steatohepatities progression and HCC transformation. Overexpression of FGF19/FGF receptor 4 significantly correlated with epithelial cell adhesion molecule (EpCAM) as a marker of hepatic cancer stem cells within the fatty liver-steatosiscirrhosis-HCC sequence in clinical patients. It is also unknown as to the potential anticancer mechanisms by which FGF21 could negatively feedback on the Th17-IL-17 axis and the carcinogenetic signaling to abolish the carcinogenetic transformation from NASH to HCC. All the previous studies build upon this scientific premise, which leads to our hypothesis that endocrine FGFs prevent NASH-HCC through negative feedback on the Th17-IL-17 axis to inhibit inflammation, control lipolysis and excessive FFAs, and eliminate the tumor initiating cells. The hypothesis will be tested in the following Specific Aims. Aim 1: To investigate the mechanism(s) of NASH-HCC transition in mice. 1) NASH-HCC model will be reproduced in C57BL/6J mice using high-fat diets (HFD), methionine-choline-deficient diets (MCD) and diethylnitrosamine (DEN); 2) NASH-HCC will be evaluated by histology, NASH score, and the biomarkers of inflammation and HCC. Aim 2: To explore the preventive/therapeutic effects of endocrine FGFs against NASH-HCC. Establishment of NASH-HCC in FGF21-KO and IL-17A mutant mice will address 1) whether FGF21 variant/FGF19 agonist can prevent WT IR and lipolysis and hepatic FFA-uptake, thereby preventing the carcinogenetic lipid-signaling; 2) whether FGF21 can suppress Th17-IL-17A axis; 3) specific anticarcinogenetic signaling of FGF21 variant/FGF19 agonist to eliminate tumor-initiating cells. This proposal will study systemically the specific anticancer effect of endocrine FGF variants on NASH-HCC transition. The importance of this proposal is, 1) to reveal therapeutic targets and the mechanism(s) during NASHHCC transition; 2) to explore pharmacological use of endocrine FGF variants against NASH-HCC.