肿瘤内癌蛋白YAP表达上调，且与肿瘤发生发展密切相关，尽管YAP依赖转录因子的下游促瘤机制研究较为明确，但YAP自身调控机制，如转录后m6A修饰调控等尚不明确。申请人前期研究发现非小细胞肺癌（NSCLC）中m6A结合蛋白YTHDC2表达下调。敲减YTHDC2能抑制YAP mRNA发生m6A修饰，阻止YAP mRNA降解，且可削弱铁死亡激活剂Erastin诱导的铁死亡；进一步研究发现敲减YAP也可促进NSCLC细胞铁死亡。因此，我们提出如下假说：YTHDC2可通过调控YAP mRNA的m6A修饰介导YAP mRNA降解，最终促进NSCLC铁死亡。本课题拟利用体外细胞实验、体内小鼠实验和临床组织标本检测三个层面探索YTHDC2调控YAP mRNA的m6A修饰介导NSCLC铁死亡的分子机制，为临床以铁死亡为靶点开发抗肿瘤新药提供可靠的理论依据。

The expression level of YAP in cancers are up-regulated and closely related to tumorigenesis. The downstream mechanism of YAP dependent transcription factors to promote tumour development have been clearly studied. However, the self-regulation mechanism of YAP, such as the regulation of m6A modification, is still unclear. We have found that the expression level of m6A binding protein YTHDC2 was down-regulated in non-small cell lung cancer (NSCLC). Knockdown of YTHDC2 can inhibit m6A modification of YAP mRNA while prevent YAP mRNA from degradation. Such effects attenuated ferroptosis induced by ferroptosis activator Erastin. Furthermore, knockdown of YAP also can promote ferroptosis in NSCLC cells. Therefore, we hypothesis that YTHDC2 can mediate YAP mRNA degradation by regulating YAP mRNA m6A modification to finally promote NSCLC ferroptosis. In this project, we will perform cell-based, mouse-based experiments and test clinical NSCLC tissue samples to reveal whether and how YTHDC2 promote NSCLC ferroptosis through regulating YAP mRNA m6A modification. Thereby, this project will also provide a reliable theoretical basis for the development of new anticancer drugs targeting against ferroptosis.