PEX5调节过氧化物酶体相关性铁死亡在肝癌细胞辐射敏感性调控中的作用及其机制研究

铁死亡是新发现的铁依赖性脂质过氧化物介导的细胞程序性死亡方式，而过氧化物酶体是负责脂质及活性氧代谢的细胞器，申请人初步证实：在肝癌细胞中，PEX5通过调控过氧化物酶体，影响活性氧、脂质活性氧及多不饱和脂肪酸的代谢过程，进而调控辐射后的铁死亡效应。在此基础上，本项目将进一步探索以下内容：① 表型上：体外和体内水平，进一步探究PEX5对肝癌细胞辐射抗性的影响；② 机制上：进一步研究PEX5/过氧化物酶体是否通过铁死亡效应而影响肝癌细胞的辐射抗性；PEX5/过氧化物酶体是否通过多不饱和脂肪酸、活性氧及脂质活性氧的代谢过程而影响辐射后的铁死亡效应；③ 临床上：收集患者样本，研究PEX5表达水平、多不饱和脂肪酸水平与放疗效果、临床预后的相关性；④ 转化应用上：探究沉默PEX5联合铁死亡诱导剂是否利于克服肝癌细胞的辐射抗性。该研究对揭示肝癌细胞辐射敏感性的调控机制，开发新的靶点药物，具有重要意义。

Ferroptosis is a newly discovered way of programmed cell death mediated by iron dependent lipid peroxide, and peroxisome is responsible for the metabolism of lipid and reactive oxygen species (ROS). We has preliminarily confirmed that PEX5 regulates the metabolism of ROS, lipid ROS and polyunsaturated fatty acids (PUFA) in liver cancer cells by regulating peroxisome function, thus regulating radiation induced ferroptosis. On this basis, this project will further explore the following contents: 1. Phenotypically: to further explore the effect of PEX5 on the radioresistance of hepatoma cells in vitro and in vivo; 2. Mechanically : to further study whether PEX5 / peroxisome affects the radiation resistance via the ferroptosis effect; to further study whether PEX5 / peroxisome affects the radiation induced ferroptosis by regulating the metabolic process of PUFA, ROS and lipid ROS; 3. Clinically: to collect patient samples and study the correlation between PEX5 expression level, PUFA level and clinical prognosis; 4. On application: to explore whether silencing PEX5 combined with ferroptosis inducer is beneficial to overcome the radiation resistance of hepatoma cells. This study is of great significance to reveal the regulatory mechanism of radiosensitivity of hepatoma cells and develop new targeted drugs to sensitize hepatoma cells to radiation therapy.