ZCCHC4介导的28S rRNA m6A甲基化通过SLC7A11调控小细胞肺癌铁死亡和化疗耐药的机制研究

化疗耐药一直以来都是小细胞肺癌（SCLC）治疗失败的主要原因，导致SCLC五年总生存率只有7%左右。近年研究发现m6A甲基化修饰和铁死亡在肿瘤化疗耐药过程中均扮演重要角色，但二者之间是否存在调控关系，以及其在SCLC化疗耐药过程中的功能和分子机制尚没有报道。本项目前期聚焦m6A甲基化修饰相关基因，首次发现m6A甲基转移酶ZCCHC4在SCLC组织和化疗耐药的细胞株中显著高表达并可降低SCLC细胞对一线化疗药物顺铂和依托泊苷的敏感性；初步机制探索发现ZCCHC4介导的28S rRNA m6A甲基化可促进铁死亡通路关键蛋白SLC7A11翻译。本项目拟在前期研究基础上进一步揭示ZCCHC4调控SCLC铁死亡通路活性和化疗耐药的分子机制，明确化疗耐药SCLC细胞中ZCCHC4表达上调的上游调控关系，探索ZCCHC4及相关基因作为诊疗靶点的临床应用潜力，为化疗耐药的SCLC的治疗提供新的思路。

Chemotherapy resistance has long been the main reason for treatment failure in small cell lung cancer (SCLC), resulting in an overall five-year survival rate of only about 7% in SCLC. Recent studies have found that N6-methyladenosine (m6A) modification and ferroptosis play important roles in chemoresistance, but whether there is a crosstalk between them, and their functions and molecular mechanisms in SCLC chemoresistance have not been reported. In this project, we focused on m6A methylation modification-related genes and found for the first time that m6A methyltransferase ZCCHC4 was significantly overexpressed in SCLC tissues and chemo-resistant cell clones and reduced the sensitivity of SCLC cells to first-line chemotherapeutic drugs cisplatin and etoposide; further preliminary mechanistic exploration revealed that ZCCHC4-mediated 28S rRNA m6A methylation promotes the translation of SLC7A11, a key protein of the ferroptosis pathway. This project aims to further reveal the molecular mechanism of ZCCHC4 on ferroptosis pathway activity and chemoresistance of SCLC based on previous studies, to clarify the upstream regulation of ZCCHC4 expression in chemo-resistant SCLC cells, and to explore the clinical application potential of ZCCHC4 and related genes as therapeutic targets, which may provide new perspective for the treatment of SCLC.