逆转化疗耐药是改善小细胞肺癌（SCLC）患者预后的关键。我们前期利用CRISPR/Cas9-sgRNA全基因组敲除、高内涵功能筛选、全外显子测序等技术发现类泛素化特异性蛋白酶SENP6可抑制铁死亡促进化疗耐药。还发现SENP6可与铁死亡蛋白GPX4结合，下调SENP6可提高GPX4的类泛素化（Sumo2），同时降低GPX4蛋白表达，而抑制泛素化降解则可回复SENP6对GPX4蛋白的影响。据此，我们提出假设：SENP6与GPX4结合抑制铁死亡，促进SCLC耐药。为验证假说，拟开展以下研究：<1>、利用临床样本、细胞和动物模型确证SENP6通过调节铁死亡促进SCLC耐药；<2>、机制探讨：通过CoIP、构建SENP6突变体等验证：SENP6互作于GPX4，通过降低GPX4蛋白Sumo2化，以减少GPX4蛋白泛素化降解，进而抑制铁死亡促进SCLC耐药。本项目有望为逆转SCLC耐药研究提供新靶点。

Reversing the chemoresistance of Small Cell Lung Cancer（SCLC）is a critical step to improve the prognosis of SCLC patients. Using the technologies such as CRISPR/Cas9-sgRNA for whole genome knockout, high content screening and whole exome sequencing, we found that small ubiquitin-related modifier （SUMO）specific protease 6（SENP6）could promoted the chemoresistance of SCLC by inhibiting the ferroptosis. Besides, we found that SENP6 could bind to the iron death protein glutathione peroxidase（GPX4）. Suppression of SENP6 increased the SUMO2 level of GPX4, but decreased the protein expression of GPX4. In addition, inhibition of ubiquitin degradation could repress the effect of SENP6 on GPX4 protein. Thus, we propose a hypothesis that SENP6 promotes the chemoresistance of SCLC by inhibiting the ferroptosis through GPX4. To test our hypothesis, we formulate the following studies. Firstly, the relationship between SENP6 and chemoresistance is to be verified by clinical samples, SCLC chemoresistance cells and animal models. Secondly, the experiments such as co-immunoprecipitation and construction of SENP6 mutants are performed to investigate whether SENP6 promotes the chemoresistance of SCLC by inhibiting the ferroptosis through GPX4. The specific way that SENP6 affection on GPX4 may be like this: SENP6 suppressed the SUMO2 level of GPX4, so reducing the GPX4 ubiquitination degradation. We may provide a new method to reverse the chemoresistance of SCLC by targeting the expression of SENP6.