肺癌是我国第一大癌症，寻找新的高效低毒抗肺癌药物具有重大意义。我们前期筛选出天然植物来源毛钩藤碱(Hirsutine)具有良好的选择性抗肺癌活性，具有开发成为高效低毒的抗肺癌新药潜力，但其选择性抗肺癌分子机制尚不明确。我们预实验发现毛钩藤碱可去磷酸化激活肺癌高表达的CAP1，诱发CAP1依赖的线粒体分裂，导致细胞色素C释放和细胞凋亡，从而发挥选择性抗肺癌作用。但CAP1调控线粒体分裂的机制尚不清楚，综合文献和我们前期研究结果提示CAP1可能是在线粒体分裂位点与Cofilin相互作用解聚F-actin，逐渐缩短F-actin长度，引起分裂复合物环收缩，最终缢裂线粒体。本项目拟在细胞系、动物、患者原代细胞多层次进一步明确毛钩藤碱的选择性诱导肺癌细胞凋亡作用，并阐明毛钩藤碱激活CAP1调控线粒体分裂的分子机制。本项目将加深对线粒体分裂的理论认识，为肺癌的治疗提供新的靶点和干预方法。

Lung cancer is the most common incident cancer and the leading cause of cancer death in China. It is of great significance to find novel anti-lung cancer drugs with high efficiency and low toxicity. Our preliminary experiments found that natural compound Hirsutine selectively induced apoptosis in lung cancer cells but with little toxicity in normal cells, indicating that Hirsutine has the potential to be developed as a new anti-lung cancer drug with high efficacy and low toxicity, but the molecular mechanism of its anti-lung cancer activity is not clear. Our preliminary experiments revealed that Hirsutine induces CAP1 (a protein highly expressed in lung cancer) dephosphorylation/activation, leading to mitochondrial fission, cytochrome c release and eventually apoptosis. However, the molecular mechanism by which CAP1 regulates mitochondrial fission remains unclear. The literatures and our preliminary results suggest that CAP1-regulated mitochondrial fission depends on its actin depolymerization activity through interaction with cofilin at the mitochondrial fission site, gradually shortening the length of F-actin, causing the contraction of the complex ring, and finally leading to mitochondrial fission. In this proposal, we aim to clarify Hirsutine’s selective anti-lung cancer activity and elucidate the molecular mechanism underlying the anti-lung cancer effects of Hirsutine through activation of CAP1-mediated mitochondrial fission. Our study will strengthen the understanding of mitochondrial fission, and provide novel targets and intervention strategy for lung cancer treatment.