HSP90α/IDH1信号调控脂质过氧化参与肝癌细胞铁死亡的机制研究

At present, drug treatment poses a substantial obstruction to improving outcomes of patients with liver cancer worldwide; such dilemma is mainly closely related to tumor evolution-induced heterogeneity. Hence, there is an urgent need to the compositional and functional understanding of tumor heterogeneity. Tumor cells often display the feature of chaperon addiction, which has been recognized as the vulnerability of tumor heterogeneity. HSP90 facilitates the stabilization of various co-chaperone conformational states by ATPase regulation and may be a potential target against tumor heterogeneity. Our previous study found that the inhibition of HSP90α activity downregulated IDH1 protein, induced lipid peroxidation, and participated in the ferroptosis of liver cancer cells, but its underlying mechanism is not clear. The aim of this proposal is to clarify the specific molecular mechanism of HSP90α regulating IDH1 protein homeostasis from three aspects of molecular chaperones and substrate complexes, exosomes and kinase pathways, and how to influence lipid peroxidation and regulate ferroptosis in liver cancer cells; furtherly, attempt to some exploratory therapeutic strategies through using HSP90 inhibitors, ferroptosis agonists and HSP90α / IDH1 signal inhibitors in different animal models or patient-derived cells with various mutation and drug resistance landscapes. The proposal belongs to the category of "free exploration" and is a hypothesis-driven research, which does not only promote the understanding of liver cancer heterogeneity in the context of tumor cell evolution, but also provides new ideas and targets for explorative drug treatment of liver cancer.

目前，肝癌药物治疗仍是全球所面临的巨大挑战，主要与肿瘤演进导致的异质性密切相关；“分子伴侣成瘾”则是肿瘤异质性的薄弱点。HSP90作为一种ATP依赖的伴侣蛋白，可能是对抗肿瘤异质性的潜在靶点。我们前期研究发现HSP90α的活性抑制可下调IDH1蛋白，介导脂质过氧化，参与肝癌细胞铁死亡，但其内在机制并不清楚。本项目拟在此基础上，从分子伴侣及底物复合体、外泌体、激酶通路等层面，明确HSP90α调控IDH1蛋白稳态的具体分子机制，进而如何影响脂质过氧化并调节肝癌细胞铁死亡；进一步利用HSP90抑制剂、铁死亡激动剂及HSP90α/IDH1信号抑制剂在突变信息及耐药背景不同肝癌动物模型及临床患者来源肝癌细胞中进行一些探索性治疗。本项目属于“自由探索范畴”、假说推动的研究，其顺利开展不但可以加深对肝癌异质性的理解，而且将为肝癌的探索性药物治疗提供新的思路及靶点。

目前，肝癌药物治疗仍是全球所面临的巨大挑战，主要与肿瘤演进导致的异质性密切相关；“分子伴侣成瘾”则是肿瘤异质性的薄弱点。HSP90α作为一种ATP依赖的伴侣蛋白，可能是对抗肿瘤异质性的潜在靶点。我们前期研究发现HSP90α的活性抑制可下调IDH1蛋白，介导脂质过氧化，参与肝癌细胞铁死亡，但其内在机制并不清楚。本项目在此基础上，从分子伴侣及底物复合体、激酶通路等层面，明确HSP90α调控IDH1蛋白稳态的具体分子机制，进而如何影响脂质过氧化并调节肝癌细胞铁死亡；进一步利用HSP90抑制剂、铁死亡激动剂及HSP90α/IDH1信号抑制剂在突变信息及耐药背景不同肝癌动物模型及临床患者来源肝癌细胞中进行一些探索性治疗。在本项基金的资助下，通过四年的科学实验，该项目取得以下重要研究结果及目标：.（1）.明确了耐药背景不同肝癌细胞内HSP90α调控IDH1蛋白稳态的分子机制及共性特征；.（2）.解析了肝癌细胞内HSP90α对IDH1蛋白表达及稳态的调控及其调节铁死亡的内在机制；.（3）.探索了靶向“HSP90α/IDH1 -铁死亡”轴在逆转肝癌耐药过程中的治疗价值；.（4）.进一步探讨了HSP90α/IDH1信号调控脂质代谢参与肝癌细胞竞争及衰老的分子机制，并且明确了HSP90α相关分子HSF1、LRP1B与SLC35A2在肝癌中的作用。.以上研究结果表明，肝癌细胞内HSP90α可通过调控IDH1蛋白稳态，促进脂肪酸β氧化及ROS，从而激活脂质过氧化，导致铁死亡，最终达到抑制肝癌生长的目的。本项目的研究成果不但可以加深对肝癌异质性的理解，而且将为肝癌的探索性药物治疗提供新的思路及靶点。