流行病学调查证实糖脂异常是肝癌发生发展的独立危险因素，但具有降糖调脂作用的桑叶总生物碱抗肝癌研究甚少，机制也不明确。甲羟戊酸途径重要调节子SREBP-2是肝癌治疗潜在靶点，我们前期研究发现桑叶总生物碱可下调SREBP-2转录活性、降低肝癌细胞中胆固醇水平并伴随细胞铁死亡，文献证实铁死亡与甲羟戊酸途径密切相关。据此，我们推测桑叶总生物碱可通过抑制SREBP-2调控甲羟戊酸途径诱导肝癌细胞铁死亡。本项目拟在分子及细胞层面揭示桑叶总生物碱抑制SREBP-2转录活性的确切机制，明确其抑制SREBP-2后肝癌细胞中铁死亡调控因子、甲羟戊酸途径异戊二烯类中间体水平及相关酶的表达变化，进而阐明桑叶总生物碱通过抑制甲羟戊酸途径诱导肝癌细胞铁死亡的机制；在动物层面考察桑叶总生物碱抑制SREBP-2诱导肝癌细胞铁死亡作用。本项目将阐明桑叶总生物碱诱导肝癌细胞铁死亡的机制，为将其应用于肝癌临床治疗提供理论依据。

Glycolipid abnormality is an independent risk factor for hepatocellular carcinoma development by epidemiological investigation. The alkaloids of mulberry leaf could display anti-hyperglycemic and lipid-regulating effects. However, there is little research on anti-hepatocellular carcinoma effects of alkaloids of mulberry leaf, and the mechanism of anti-hepatocellular carcinoma effects of alkaloids of mulberry leaf is still not clear. Sterol regulatory element binding protein-2 (SREBP-2), which is the major regulator of mevalonate pathway, could act as a potential therapeutic target for hepatocellular carcinoma treatment. Our previous studies have verified that alkaloids of mulberry leaf could significantly down-regulate SREBP-2 transcriptional activity, accompanied by the decrease cholesterol level in hepatocellular carcinoma cells as well as cell ferroptosis, and ferroptosis has been reported to be closely associated with mevalonate pathway. Therefore, we hypothesize that alkaloids of mulberry leaf could induce ferroptosis of hepatocellular carcinoma cells by inhibiting SREBP-2 to regulate mevalonate pathway. In this project, we plan to reveal the exact mechanism by which alkaloids of mulberry leaf inhibit the transcriptional activity of SREBP-2 at the molecule and cellular level, and clarify the changes of expression of ferroptosis regulatory factors, changes concentration of isoprene intermediates and expression of related enzymes in the mevalonate pathway. All the results above could assist us to clarify the ferroptosis mechanisms of alkaloids of mulberry leaf induced by inhibiting mevalonate pathway in vitro. Finally, we will confirm the anti-tumor effects of alkaloids of mulberry leaf resulted by ferroptosis by inhibiting SREBP-2 in vivo. In conclusion, we aim to clarify the molecular anti-hepatocellular carcinoma mechanism of alkaloids of mulberry leaf and provide theoretical basis for its application in the clinical treatment of hepatocellular carcinoma.