肝内胆固醇积累和高胆固醇血症与肝细胞癌（HCC）相关。然而，胆固醇降低药物对HCC的治疗效果存在争议，表明胆固醇代谢与HCC的关系比预期更为复杂。c-Myc小鼠肿瘤形成了胆固醇合成和戊糖磷酸途径（PPP）之间的正反馈，而不是糖酵解。阻断PPP阻止了c-Myc小鼠的胆固醇合成和HCC的发生，而消除糖酵解不影响胆固醇合成，也无法阻止c-Myc引起的HCC。令人意外的是，胆固醇合成和PPP的限速酶3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）和葡萄糖-6-磷酸脱氢酶（G6PD）被识别为microRNA-206的直接靶点。通过靶向Hmgcr和G6pd，microRNA-206中断了正反馈并完全阻止了c-Myc小鼠的HCC，而100％的对照小鼠死于HCC。中断microRNA-206与Hmgcr和G6pd的相互作用恢复了由miR-206抑制的胆固醇合成、PPP和HCC生长。本研究发现了胆固醇合成和PPP之间以前未描述的正反馈环路，驱动HCC，而microRNA-206通过中断此环路来预防HCC。作为过程而非胆固醇本身是HCC的主要贡献者。© 2023.作者。

Hepatic cholesterol accumulation and hypercholesterolemia are implicated in hepatocellular carcinoma (HCC). However, the therapeutic effects of cholesterol-lowering drugs on HCC are controversial, indicating that the relationship between cholesterol metabolism and HCC is more complex than anticipated. A positive feedback between cholesterol synthesis and the pentose phosphate pathway (PPP) rather than glycolysis was formed in tumors of c-Myc mice. Blocking the PPP prevented cholesterol synthesis and thereby HCC in c-Myc mice, while ablating glycolysis did not affect cholesterol synthesis and failed to prevent c-Myc-induced HCC. Unexpectedly, HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) and G6PD (glucose-6-phosphate dehydrogenase), the rate-limiting enzymes of cholesterol synthesis and the PPP, were identified as direct targets of microRNA-206. By targeting Hmgcr and G6pd, microRNA-206 disrupted the positive feedback and fully prevented HCC in c-Myc mice, while 100% of control mice died of HCC. Disrupting the interaction of microRNA-206 with Hmgcr and G6pd restored cholesterol synthesis, the PPP and HCC growth that was inhibited by miR-206. This study identified a previously undescribed positive feedback loop between cholesterol synthesis and the PPP, which drives HCC, while microRNA-206 prevents HCC by disrupting this loop. Cholesterol synthesis as a process rather than cholesterol itself is the major contributor of HCC.© 2023. The Author(s).