Klotho基因具有抑制正常细胞衰老和抑制肺癌细胞增殖、迁移的双重作用，但其机制尚不明确。衰老相关分泌表型（SASP）与肺癌发生发展密切相关，其中衰老相关炎症因子以及IL-6/Stat3、IL-6/p53等信号通路具有重要作用；klotho可通过调控RIG-I/PAI-1等信号，抑制衰老相关炎症因子表达。我们前期研究发现klotho不仅具有直接抑制肺癌作用，klotho还可调控衰老成纤维细胞相关炎症因子的释放，从而抑制肺癌细胞增殖、迁移。因此，我们推测klotho可能通过调控SASP，间接抑制肺癌发生发展。为验证此假设，本项目将从整体和细胞水平研究klotho是否通过调控衰老成纤维细胞RIG-I/PAI-1等信号改变SASP，进而通过调节IL-6/Stat3、IL-6/p53等信号，抑制肺癌发生发展。预期研究结果将进一步揭示klotho抑制肺癌发生发展的作用及机制，为肺癌防治提供新思路。

Anti-aging gene klotho not only inhibits normal cell senescence, but also inhibits the proliferation and migration of lung cancer cells. The gene plays a dual role in aging and cancer, yet the specific contact mechanism is not clear. Studies have found that senescence-associated secretory phenotype (SASP) plays an important role in tumorigenesis, of which senescence-associated inflammatory factor and IL-6/Stat3 and IL-6/p53 pathways were especially significant; Klotho can inhibit senescence-associated inflammatory factor production through regulating RIG-I/PAI-1 signal. Our previous data indicates that klotho can not only directly inhibit lung cancer, but can also effectively control the release of senescent fibroblasts-associated inflammatory factor, which ultimately inhibits lung cancer cell occurrence and development. Thus, we presume that klotho may indirectly inhibit tumorigenesis by regulating SASP. In this project, we will use senescent cell and animal tumor model to explore whether klotho can inhibit the release of SASP by regulating RIG-I/PAI-1 signal, influence IL-6/Stat3 and IL-6/rRNA/p53 pathways, and eventually inhibit the growth and migration of lung cancer cells. The results of this project will serve as a foundation for future development of novel therapeutic interventions for lung caner and aging.