华泽兰调控FTH-NCOA4-LC3信号轴诱导铁蛋白自噬性降解促进肝癌铁死亡作用及机制研究

铁死亡是近几年报道的铁离子依赖性细胞死亡方式，诱导铁死亡是高效杀灭肝癌等恶性肿瘤的可行思路。然而铁的增加会促进铁蛋白生成，储存多余的铁。课题组前期研究发现具有清热解毒、疏肝活血功效的华泽兰中倍半萜有效部位具有抗肝癌作用，通过促进游离铁生成，短暂上调铁蛋白（FTH）随后降低其表达，增加核受体共激活因子4（NCOA4）与自噬蛋白LC3表达，诱导铁死亡。基于这一发现，提出“华泽兰倍半萜有效部位促进游离铁释放，激活FTH-NCOA4-LC3介导的铁蛋白自噬使铁蛋白降解，再次释放游离铁，诱导肝癌产生铁死亡”的假说。本项目拟重点从FTH-NCOA4-LC3信号轴介导的铁蛋白自噬展开研究，并从基因转录和蛋白质稳态调控阐明其活化NCOA4具体机制。旨在揭示华泽兰倍半萜有效部位诱导肝癌产生铁死亡新型作用机制，为进一步理解铁死亡发生机制提供一种思路，也为设计基于铁蛋白自噬的新型抗肝癌中药研发提供科学依据。

Ferroptosis is a kind of iron-dependent programmed cell death reported in recent years. Inducing ferroptosis is a feasible way to effectively kill hepatocellular carcinoma (HCC) or other malignant tumors. However, the increase of iron will promote the accumulation of ferritin and store excess iron. According to the theories of traditional Chinese medicine (TCM), the project team selected the Eupatorium Chinense L., which has these effects of “heat-clearing and detoxifying” and “liver-discharging and blood-activating”, and for the first time, found an active fraction of sesquiterpenoids by tracking anti-HCC activity in vivo and in vitro. The sesquiterpenoids induced ferroptosis by promoting the content of free iron, increasing the expression of ferritin (FTH) temporarily and then decreasing, upregulating the expression of nuclear receptor coactivator 4 (NCOA4) and autophagy protein LC3. Based on this, we hypothesize that the sesquiterpenoids can promote the accumulation of free iron, increase ferritinophagy through FTH-NCOA4-LC3 signal axis, release free iron again and induce ferroptosis eventually. This team will continue to study the effect of the sesquiterpenoids on ferritinophagy mediated by FTH-NCOA4-LC3 signal axis and clarify the activation of NCOA4 from gene transcription and protein homeostasis regulation. This study can not only reveal the mechanism of ferritinophagy induced by the sesquiterpenoids to provide a new idea for further understanding the mechanism of ferroptosis, but also provide a scientific basis for the design of new TCM against HCC based on ferroptosis.