肺腺癌目前仍缺乏有效的靶向治疗药物，而铁死亡是肿瘤治疗的新靶点，lncRNAs在铁死亡中的作用和机制远未明确。申请者前期发现lncRNA-LINC00641在肺腺癌组织中表达下调，且与较晚的分期和较差的预后相关，初步功能研究提示LINC00641可能在肺腺癌中促进铁死亡发挥抑癌作用。LINC00641在肺腺癌中主要定位于细胞核，可结合HuR蛋白并影响HuR蛋白在胞浆、胞核中的分布，提示LINC00641可能通过HuR蛋白发挥作用。基于前期预实验、生物信息学分析，结合文献证据，我们推测LINC00641可结合HuR蛋白，进而抑制细胞核中HuR蛋白转运至细胞浆，然后下调铁死亡关键抑制因子GPX4和FSP1的表达促进细胞铁死亡，在肺腺癌中发挥抑癌作用。为验证该假说，本项目拟从人群、动物、细胞及分子水平研究铁死亡相关的LINC00641在肺腺癌中的作用及分子机制，为肺腺癌的诊治提供新的靶点。

Lung adenocarcinoma still lacks effective targeted therapies, and targeting ferroptosis is a new promising way for cancer therapy. The role and mechanism of most lncRNAs in ferroptosis are still unclear. We found that lncRNA-LINC00641 was significantly down regulated in lung adenocarcinoma, and its low expression was correlated with late stage and poor prognosis. Preliminary functional studies suggested that LINC00641 could promote ferroptosis and act as a tumor suppressor in lung adenocarcinoma. LINC00641 was mainly located in the nucleus of lung adenocarcinoma cells. LINC00641 could bind to HuR and regulate HuR distribution in cytoplasm and nucleus, suggesting LINC00641 may exert its function through HuR. Based on previous experiments, bioinformatics analysis and available evidence, we hypothesize that LINC00641 binds to the HuR and inhibits the translocation of HuR from the nucleus to the cytoplasm, and then down-regulates the expression of GPX4 and FSP1 to promote ferroptosis in lung adenocarcinoma. To verify the hypothesis, this project intends to explore the biological function and molecular mechanism of LINC00641 at multiple levels, and provides new effective diagnostic markers and therapeutic targets for lung adenocarcinoma.