铁硫蛋白CISD2通过代谢重编程调控Keap1-NRF2-FTH信号轴介导RAS突变肿瘤细胞铁死亡的机制研究

铁死亡是一种新发现的依赖铁的程序性死亡方式，其具体调控机制仍有待完善。现有研究表明RAS突变肿瘤细胞更易发生铁死亡，为靶向RAS突变的癌症疗法提供新的方向。我们已发表成果证实：具有调节铁稳态及氧化损伤功能的铁硫蛋白与铁死亡具有紧密的联系（Redox Biology, 2020）。我们最近发现：①在RAS突变细胞中敲低铁硫蛋白CISD2的表达可诱导铁死亡的发生；②敲低CISD2后，破坏线粒体稳态，线粒体能量代谢发生转变；③敲低CISD2激活自噬，下调Keap1-NRF2-FTH通路，促进自由铁的累积。因此，我们拟通过体内、外实验证实如下科学假说：CISD2蛋白缺失后通过线粒体代谢重编程，下调自噬介导的Keap-NRF2-FTH信号轴，诱导自由铁累积，激活铁死亡的发生。通过课题实施预期阐明CISD2调控铁死亡的机制，最终为开发相关的治疗方案提供新的思路和理论依据。

Ferroptosis is a newly discovered type of programmed cell death, with a typical characteristic of iron-dependent lipid peroxidation. However, the underlying mechanisms remain largely unknown and need further study. Previous studies have shown that RAS mutated tumor cells are more prone to ferroptosis, providing a new direction for cancer therapies targeting RAS mutations. Our published papers have evidenced that the iron-sulfur proteins with the function of regulating iron homeostasis and oxidative damage are closely associated with ferroptosis (Redox Biology, 2020). Furthermore, we recently found that (1) ferroptosis can be induced in RAS mutant cells by knockdown of iron-sulfur protein CISD2; (2) mitochondrial homeostasis was destroyed and energy metabolism was transformed in CISD2 knockdown cells; (3) autophagy was activated in CISD2 knockdown cells with the down-regulation of Keap1-NRF2-FTH pathway, promoting the accumulation of free iron. Therefore, through in vitro and in vivo experiments, we intend to confirm the hypothesis that CISD2 deletion down-regulates autophagy-mediated Keap1-NRF2-FTH axis through mitochondrial metabolic reprogramming, inducing free iron accumulation and ferroptotic cell death. Through the implementation of this project, we aim to clarify the mechanism of CISD2 regulating ferroptosis, providing a new idea and theoretical basis for the development of related therapies.