醛氧化酶及其突变体调节肺腺癌铁死亡的研究

我国肺癌发病及死亡率均已双第一，寻找肺癌预后生物标志物和新靶点以提高疗效显得尤为重要。醛氧化酶（AOX1）与药物代谢密切相关，其在肺癌中的作用仍不清楚。我们前期发现AOX1低表达及其突变均使肺腺癌患者生存时间更短，且有可能受到淋巴细胞特异性螺旋酶（LSH）的调控。过表达AOX1可促进铁死亡，提示其在肺腺癌中发挥抑癌作用。我们将分析 AOX1 表达水平及其突变与铁死亡的相关性和参与机制，明确AOX1表达及其突变对肺腺癌细胞生物学特征及抗肿瘤药物的影响，阐明AOX1表达及其突变对内环境铁稳态和脂质活性氧的影响，确定AOX1表达及其突变通过影响NADPH/NADP+比调节铁死亡的机制，最后研究AOX1与LSH表达水平的相关性，并分析AOX1突变体结构，多维度解释对铁稳态和活性氧的影响。通过本项目的实施，将阐明AOX1及其突变体在肺癌中的作用及机制，为药物开发及已有药物的代谢机制研究提供新的靶点。

Nowadays, lung cancer ranks the most common malignancy in China, with the highest morbidity and mortality. To improve the therapy efficiency, it is crucial to investigate novel biomarkers and targets for patients with lung cancer. Aldehyde oxidase (AOX1) is closely related to drug metabolism, however, its role in lung cancer is still unclear. Our preliminary data showed that lower AOX1 expression and mutant AOX1 were associated with worse overall survival. AOX1, which is potentially regulated by LSH, promotes ferroptosis initiate, proving its antitumor role in lung adenocarcinoma (LUAD). We here will identify the role and mechanism of AOX1 expression and mutation on mediating ferroptosis, and clarify the effect of AOX1 expression and mutation on the biological characteristics of LUAD cells and antitumor drugs，as well as ferroptosis homeostasis and lipid ROS. Next, we will determine the mechanism of AOX1 expression and mutation regulating ferroptosis though affecting the ratio of NADPH/NADP+. Finally, we will identify the correlation between AOX1 and LSH, and anlayze the structure of mutant AOX1, to clarify the role of AOX1 on ferroptosis homeostasis and ROS from multiple aspects. Through this project, we will discover the role and mechanism of AOX1 expression and mutation in lung cancer, which provides novel insights and scientific basis in drug development and existed drug metabolic mechanism.