长链非编码RNA AFAP1-AS1竞争性结合KEAP1诱导肝内胆管细胞癌拮抗铁死亡的研究

肝内胆管细胞癌（ICC）是一种恶性程度极高的肝脏肿瘤，总体预后差且缺乏有效的辅助治疗手段，其发生机制仍不明确。近年来，诱导肿瘤铁死亡被发现是极具潜力的肿瘤治疗策略，寻找调控铁死亡的分子元件从理论和实践上均有重大意义，而目前铁死亡在ICC中的生理意义尚不清晰，也鲜有LncRNA调控铁死亡的相关研究报道。本团队通过RNA组学分析及功能筛选，发现ICC中高表达的AFAP1-AS1可通过与NRF2竞争性结合KEAP1而调节脂质代谢及铁死亡通路，继而介导ICC的发生发展，提示其可能具备ICC特异性检测或干预靶点的潜力。本项目拟在动物及细胞分子水平进一步检验其在ICC发生发展中的作用，深入研究其对铁死亡的调控机理，明确其与KEAP1的相互作用模式，探索TET家族蛋白对其去甲基化的调控机制，并评估金纳米棒荷载siRNA技术体内干预AFAP1-AS1的治疗价值，为ICC治疗靶点的开发及临床应用提供依据。

Intrahepatic cholangiocarcinoma (ICC) is a highly malignant liver tumor with poor overall prognosis and lack of effective adjuvant therapy. The mechanism of its occurrence is still unclear. In recent years, the induction of ferroptosis in tumors has been found to be a very promising tumor treatment strategy. Finding the molecular elements that regulate ferroptosis is theoretically and practically significant. At present, the physiological significance of ferroptosis in ICC is unclear. There are few reports about LncRNA regulating ferroptosis. Through RNAomics analysis and functional screening, our team found that AFAP1-AS1, which is highly expressed in ICC, can regulate lipid metabolism and ferroptosis pathways by competitively binding to KEAP1 against Nrf2, and then mediate the occurrence and development of ICC, suggesting that it may have potential for specific detection or intervention of targets for ICC. This project intends to further test its role in the occurrence and development of ICC both in vivo and in vitro, explore its regulatory mechanism on ferroptosis, clarify its interaction mode with KEAP1, and explore the role of TET family proteins in its demethylation regulating mechanism, and evaluate the therapeutic value of gold nanorod-loaded siRNA technology in vivo intervention of AFAP1-AS1, providing a basis for the development of ICC therapeutic targets and clinical application.