代谢酶IDH突变促进细胞铁死亡敏感性的机制研究

铁死亡是新近发现的一种细胞死亡方式，它在死亡形态与发生机制上都与其它已知的死亡方式不同，主要由铁依赖的脂质过氧化物累积诱导发生。铁死亡已被发现参与神经退行性疾病、缺血再灌注损伤以及肿瘤细胞恶性转化与转移等病理过程，然而目前对其机制和生理功能的认知仍十分有限。本研究组在前期实验中，发现参与三羧酸循环的异柠檬酸脱氢酶（IDH）的突变可导致细胞对铁死亡更加敏感，据此提出关于铁死亡调控机制的全新假设。IDH是一种在多种肿瘤中高频突变的代谢酶，IDH突变导致致癌代谢物2-HG的产生，它可竞争性抑制多种α-KG依赖的双加氧酶，进而影响多种生物学过程。我们在该项目中将利用多种含IDH突变的肿瘤细胞模型，验证IDH突变和2-HG累积与铁死亡敏感性的关系，重点研究2-HG通过影响参与铁死亡调控的双加氧酶而促进铁死亡的可能机制，并探讨通过诱导铁死亡抑制含IDH突变的肿瘤发生的可能性，为肿瘤治疗提供新的线索。

Ferroptosis is a newly defined form of cell death. It is distinct from other forms of cell death on both cell morphology and molecular mechanism. Ferroptosis is induced by the accumulation of lipid peroxide (lipid-ROS), a process that is iron dependent. Ferroptosis has been found to participate in multiple pathological processes, including neuron degenerative diseases, ischemia/reperfusion injury, and tumor cell transformation and invasion. However, our current knowledge about the regulatory mechanism and physiological functions of ferroptosis is still limited. We found in our pilot study that the mutation of isocitrate dehydrogenase (IDH), the enzyme catalyzing conversion of isocitrate to α-ketoglutarate (α-KG) in the TCA cycle, sensitize cells to ferroptosis. IDH is frequently mutated in several types of cancers, resulting in the production of 2-hydroxyglutarate (2-HG), which is an oncometabolite that interferes with various α-KG dependent dioxygenases in multiple biological processes. In this proposal, we will take advantage of several cancer cell lines that bear IDH mutation to further study the effect of IDH mutation and 2-HG accumulation on ferroptosis sensitivity. In addition, we will elucidate the possible mechanism that 2-HG promotes ferroptosis sensitivity through interfering some dioxygenases that participate in ferroptotic regulation. We will also investigate the potential application of ferroptosis inducers in treating tumors bearing IDH mutation, which may provide new clues for cancer therapy.