SQLE is a rate-limiting enzyme for cholesterol biosynthesis in human. Nonalcoholic fatty liver disease (NAFLD)–induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed world. RNA sequencing analysis of NAFLD-HCC samples revealed squalene epoxidase (SQLE) as the top outlier metabolic gene overexpressed in NAFLD-HCC patients. It is reported that SQLE expression is associated with poor survival of HCC patients. SQLE overexpression caused a more notable rise in cholesteryl esters and activated the PTEN/PI3K/AKT/mTOR signaling cascade to drive carcinogenesis in NAFLD-HCC cell lines。Cholesteryl esters were able to induce NAFLD-HCC cell growth. The data indicate that terbinafine(SQLE inhibitor), by inhibiting SQLE, suppressed the accumulation of liver cholesterol/cholesteryl ester and blocked the SQLE-ROS-DNMT3A-PTEN oncogenic axis, ultimately resulting in inhibition of hepatocarcinogenesis in Sqle transgenic mice. Pharmacological inhibition of SQLE is hence a promising approach that should be safe and effective for the prevention and treatment of NAFLD-HCC.