USP13去泛素化修饰NRF2影响肺癌自噬和铁死亡之间相互交流的研究

肺癌发病率和死亡率高，严重威胁着人类健康。细胞生存和死亡之间的平衡是机体存活的重要条件，不同的细胞命运决定方式之间存在着联系，自噬和铁死亡作为影响肺癌发生发展的两种重要的细胞命运调控方式，二者间的交互关系及机制尚不清楚。针对此问题，申请者研究发现抑制自噬同时诱导铁死亡能有效促进肺癌细胞死亡。进一步，我们发现NRF2可能是自噬和铁死亡相互交流的关键调控基因，NRF2在肺癌中高表达且主要分布于肺癌细胞细胞核内，这可能与NRF2导致的自噬激活和铁死亡的抑制有关。进一步研究发现USP13通过去泛素化稳定NRF2。基于此，本项目拟研究肺癌中自噬和铁死亡之间的相互作用以及USP13去泛素化修饰NRF2进而影响自噬和铁死亡之间的交互关系，从而促进肺癌发生发展的作用机制。通过本研究将为肺癌的诊断和治疗提供新的分子靶点和治疗方式，具有重要的基础和临床意义。

Lung cancer is the tumor with the highest morbidity and mortality in China, which seriously threatens people's health.The balance between cell survival and cell death is very important for the survival of the body.There are connections between different cell fates,Autophagy and ferroptosis are two important regulation manners of cell fate,Which both play important roles in the development of lung cancer,but the interaction and mechanism between them are still unclear.Recently,applicants discovered that combining autophagy inhibition and ferroptosis activation can induce lung cancer cell death significantly.Then,we found that NRF2 maybe the key regulator of the crosstalk between autophagy and ferroptosis,NRF2 is highly expressed and mainly localized in the nuclear of lung cancer cells which may related to the activation of autophagy and the suppression of ferroptosis induced by NRF2 and screening found that USP13 can deubiquitinate and stabilize NRF2. Based on above findings, this project intends to study the interaction of autophagy and ferroptosis in lung cancer cells,and the mechanism of interaction between autophagy and ferroptosis influenced by USP13 deubiquitination of NRF2, so as to promote the occurrence and development of lung cancer.This study will provide new molecular targets and therapeutic approaches for the diagnosis and treatment of lung cancer, which has important basic and clinical significance.