Nonalcoholic fatty liver disease (NAFLD)–induced hepatocellular carcinoma (HCC) is an emerging malignancy in the developed world; however, mechanisms that contribute to its formation are largely unknown, and targeted therapy is currently not available. Our RNA sequencing analysis of NAFLD-HCC samples revealed squalene epoxidase (SQLE) as the top outlier metabolic gene overexpressed in NAFLD-HCC patients. Hepatocyte-specific Sqle transgenic expression in mice accelerated the development of high-fat, high-cholesterol diet–induced HCC. SQLE exerts its oncogenic effect via its metabolites, cholesteryl ester and nicotinamide adenine dinucleotide phosphate (NADP⁺). Increased SQLE expression promotes the biosynthesis of cholesteryl ester, which induces NAFLD-HCC cell growth. SQLE increased the NADP⁺/NADPH (reduced form of NADP⁺) ratio, which triggered a cascade of events involving oxidative stress–induced DNA methyltransferase 3A (DNMT3A) expression, DNMT3A-mediated epigenetic silencing of PTEN, and activation of AKT-mTOR (mammalian target of rapamycin). In human NAFLD-HCC and HCC, SQLE is overexpressed and its expression is associated with poor patient outcomes. Terbinafine, a U.S. Food and Drug Administration–approved antifungal drug targeting SQLE, markedly inhibited SQLE-induced NAFLD-HCC cell growth in NAFLD-HCC and HCC cells and attenuated tumor development in xenograft models and in Sqle transgenic mice. Suppression of tumor growth by terbinafine is associated with decreased cholesteryl ester concentrations, restoration of PTEN expression, and inhibition of AKT-mTOR, consistent with blockade of SQLE function. Collectively, we established SQLE as an oncogene in NAFLD-HCC and propose that repurposing SQLE inhibitors may be a promising approach for the prevention and treatment of NAFLD-HCC.

非酒精性脂肪肝疾病（NAFLD）诱发的肝细胞癌（HCC）在发达国家是一种新兴的恶性肿瘤；然而，促成其形成的机制在很大程度上尚不清楚，目前还没有靶向治疗。我们对NAFLD-HCC样品进行的RNA测序分析显示，角鲨烯环氧酶（SQLE）是NAFLD-HCC患者中过度表达的顶级异常基因。小鼠肝细胞特异的Sqle转基因表达加速了高脂，高胆固醇饮食诱导的HCC的发展。SQLE通过其代谢产物，胆固醇酯和烟酰胺腺嘌呤二核苷酸磷酸（NADP ⁺）发挥其致癌作用。增加SQLE表达促进胆固醇酯的生物合成，其诱导NAFLD-HCC细胞生长。SQLE提高NADP ⁺ / NADPH（还原NADP的形式⁺）比率，由此引发涉及氧化应激诱导的DNA甲基3A（DNMT3A）的表达，PTEN的DNMT3A介导的表观遗传沉默，和AKT-mTOR的激活事件的级联（雷帕霉素的哺乳动物靶标）。在人类NAFLD-HCC和HCC中，SQLE过表达，其表达与患者预后不良相关。美国食品和药物管理局批准的Terbinafine靶向SQLE的抗真菌药物明显抑制了SQLE诱导的NAFLD-HCC和HCC细胞中的NAFLD-HCC细胞生长，并在异种移植模型和Sqle转基因小鼠中减弱了肿瘤的发展。特比萘芬抑制肿瘤生长与降低胆固醇酯浓度，恢复PTEN表达和抑制AKT-mTOR有关，这与SQLE功能的阻断相一致。总体而言，我们将SQLE建立为NAFLD-HCC中的致癌基因，并提出重新利用SQLE抑制剂可能是预防和治疗NAFLD-HCC的有前途的方法。