对肿瘤代谢异常进行系统研究，发现并揭示肿瘤代谢异常的关键蛋白及分子调控网络，对我国的肿瘤化学预防与靶向治疗具有重大意义。我们前期研究发现亲环素A（CypA）参与调控非小细胞肺癌（NSCLC）中丝氨酸/甘氨酸代谢，其小分子抑制剂HL001对丝氨酸/甘氨酸含量升高的NSCLC细胞具有显著的杀伤活性。初步机理研究表明，CypA可直接结合并激活转录因子Nrf2。Nrf2是细胞防御氧化应激的重要调节因子，近年来研究表明Nrf2广泛参与了肿瘤细胞的氨基酸代谢。因此，本项目拟利用代谢组学、功能基因组学、复合物晶体和NMR等手段：确证CypA和Nrf2相互作用的关键位点；明确CypA通过Nrf2调控NSCLC细胞丝氨酸/甘氨酸代谢的作用机制；构建CypA/Nrf2抑制剂筛选方法；筛选及确认CypA/Nrf2小分子抑制剂对NSCLC的增殖抑制活性。为研发新型NSCLC治疗药物提供理论基础和实验依据。

It is important to find out the driver proteins and control network in tumor cell metabolism. In our previous work, we found that in non-small cell lung cancer (NSCLC), cyclophilin A (CypA) is involved in the biosynthesis of serine/glycine. HL001- a CypA inhibitor specifically suppressed the survival of NSCLC cells which harboring an increased content of serine and glycine. Our further results indicated that CypA can directly bind and activate Nrf2. Nrf2 is a key transcription factor that regulate antioxidant defense, and has been widely reported in regulating the metabolism of cancer cells in recent years. Based on the above results, we want to further investigate the structure and bio-functions of CypA/Nrf2 complex. Which include getting the binding site information of CypA/Nrf2 and the regulation mode of CypA/Nrf2 in serine/glycine metabolism of NSCLC cells, finding out if CypA/Nrf2 complex triggers the metabolic reprogramming in NSCLC. We also need to set up the screening method searching CypA/Nrf2 inhibitors, used both cell and animal modes to clarify the anti-tumor activities of CypA/Nrf2 small molecule inhibitors in NSCLC cells. Finally, provide theoretical and experimental basis for the development of new anti-NSCLC drugs.