蛋白质翻译的错误调控是肝癌发生的关键因素，参与翻译调控的真核起始因子eIF4E在肝癌组织中高表达，促进肝癌的发生、发展。因此，eIF4E是治疗肝癌的有效靶点。然而目前靶向eIF4E的抗肿瘤药物会引起AKT的反馈激活，降低其抗肿瘤作用。我们前期研究发现结构全新的吲哚酰肼类化合物IHZ-1能够同时下调eIF4E和AKT的磷酸化水平，且此化合物具有良好的抗肝癌活性和药物选择性，提示IHZ-1可能通过调控AKT通路抑制蛋白质翻译而发挥其抗肝癌作用，从而可能解决目前蛋白质翻译抑制剂反馈激活AKT导致药效降低的问题。因此，本项目拟研究IHZ-1对PI3K-AKT-mTOR信号通路的调控和抑制AKT反馈激活的作用机制；同时研究IHZ-1对eIF4F复合体的干扰作用以及对下游调控基因的影响，并进一步在动物水平评价其抗肝癌药效。本项目的完成将为研发抑制蛋白质翻译的抗肝癌小分子化合物提供理论基础和科学依据。

Deregulation of protein translation is a key factor for hepatocarcinogenesis. The expression of eukaryotic initiation factor 4E (eIF4E) is significantly increased in HCC and the over-expression of eIF4E promotes tumor initiation and progression. Therefore, eIF4E is an efficient therapeutic target. However, targeted inhibition of eIF4E anticancer drugs can activate AKT in the feedback pathway, and reduce its anti-tumor effect. We have screened a series of indole hydrazide compounds and found that the IHZ-1 can simultaneously down regulate the expression of eIF4E and AKT, suggesting that the protein translation inhibition effects of IHZ-1 on hepatocellular carcinoma cells are associated with AKT pathway. In addition, IHZ-1 has good anti-hepatoma activity and drugs selectivity. Therefore, this finding may help to solve the translation inhibitor efficacy caused by AKT feedback activation. This study is to investigate the regulation effect of IHZ-1 on PI3K-AKT-mTOR pathway, and the mechanisms of the IHZ-1 down regulate the expression of AKT. Moreover, the role and target of the IHZ-1 on the effects of eIF4F complex will be explored. Finally the anti-hepatoma effects of the IHZ-1 will be evaluated in vivo. In conclusion, this study will provide theoretical basis for inventing the translation inhibitor with anti-hepatoma activity.