NRF2调控铁死亡在β地中海贫血发生发展中的作用及分子机制

β-thalassemia is a monogenic lethal genetic disease resulting from the deficiency of β-globin gene. Ineffective hematopoiesis and long-term transfusion lead to excessive iron deposition in multiple organs, which in severe cases can cause severe organ failure or even death. Iron is necessary for life, but can also cause cell death. Accordingly, cells evolved a robust, tightly regulated suite of genes for maintaining iron homeostasis. Ferroptosis is a recently recognized and iron-dependent form of regulated cell death and NRF2 gene plays a key oxidative stress factor that regulates the gene transcription during cell metabolism. We recently demonstrated that nuclear factor erythroid-derived 2-like 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased ferroptosis in vitro and in tumor xenograft models. These exciting findings raise several important questions regarding the previously unidentified role of NRF2 in ferroptosis.We previously demonstrated that NRF2 is also a novel iron death regulatory protein that inhibits iron death in erythroid precursors. In this proposal, our central hypothesis is that NRF2 inhibits ferroptosis in erythroid precursor cells which in turn limits development of β-thalassemia. To test this hypothesis, we will use transgenic animal, mediterranean anemia derived iPS cells as the main research materials to identify the role of NRF2 in ferroptosis by gene intervention, hematopoietic differentiation and allograft. We will exploit molecular, cellular, and animal models to pursue the following aims. Aim 1: Identify intracellular effectors responsible for NRF2 activity in ferroptosis. Aim 2. Identify extracellular effectors responsible for NRF2 activity in ferroptosis. Aim 3. Evaluate the efficacy of targeting NRF2 by drugs in the spontaneous murine model for β-thalassemia. Aim 4. Evaluate the efficacy of targeting NRF2 by knockout in the spontaneous murine model for β-thalassemia. The completion of these exciting studies will not only identify a potential strategy for β-thalassemia therapy, but also provide new perspectives on the mechanism of ferroptosis.

β地中海贫血(β地贫)是β珠蛋白基因缺陷导致的单基因致死性遗传病。由于其无效造血及长期输血会引起多脏器过度铁沉积，严重时引起器官功能衰竭甚至死亡。铁死亡是一种新发现铁依赖性的细胞死亡形式。NRF2是一种氧化应激表达的关键转录因子。申请者前期研究表明NRF2也是一种新型的铁死亡调节蛋白，且能够抑制红系前体细胞铁死亡。以此为基础，本人提出“NRF2抑制红系前体细胞铁死亡发生，从而影响β地贫发生和发展”的假说。针对此假说，本项目拟选用转基因动物、β地贫iPS疾病模型细胞为主要研究材料，采用基因干预、造血分化、异体移植等方法，在动物、细胞和分子水平，深入探讨NRF2通路调控铁死亡的分子机制，进而探索NRF2通路在β地贫发生发展中的作用，为铁死亡的研究开辟新的领域。本项目可望揭示NRF2在β地贫的作用机制，为寻找β地贫治疗药物和检测手段提供新的思路与实验线索，具有重要的科学意义和潜在的应用前景。

β-地中海贫血（简称β-地贫）是由于β-珠蛋白基因缺陷导致β-珠蛋白合成障碍导致的溶血性贫血。β-地贫无效造血和频繁输血导致过多的铁沉着于肝脏、心脏、胰腺等器官，从而引起严重器官损伤。铁死亡（Ferroptosis）是一种铁依赖性的，区别于细胞凋亡、细胞坏死、细胞自噬的新型细胞程序性死亡方式。本项目探讨了靶向铁死亡对β-地贫发生发展的作用及其分子机制。我们研究发现，NRF2杂合缺失未加重β-地贫小鼠的贫血表型；铁死亡诱导剂未加重β-地贫小鼠的贫血表型；铁死亡抑制剂（黄芩素）未缓解β-地贫小鼠的贫血表型，但缓解了β-地贫小鼠肝脏铁过载损伤。进一步研究，我们发现黄芩素可以逆转RSL3造成的肝细胞铁死亡，并能显著恢复β-地贫小鼠肝脏的铁离子含量、MDA和GSH水平。从机制上讲，黄芩素可能通过激活NRF2抗氧化途径和增加下游GPX4的表达，进而起到抗铁死亡从而保护肝细胞的作用。本课题证明了黄芩素对β-地贫模型小鼠肝脏铁过载损伤的保护作用，为治疗β-地贫肝脏铁过载提供一种潜在的候选药物。

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