氟伐他汀通过ferroptosis与自噬抑制肺腺癌骨转移的作用和机制研究

骨转移是肺癌最常见的并发症之一，而现有的抗骨转移药物存在较多缺陷，寻找新的高效低毒的抗骨转移疗法是当前医学研究亟待解决的问题。我们前期研究发现，氟伐他汀可在肺腺癌细胞中诱发自噬，并以自噬依赖的方式抑制癌细胞向骨组织转移。近期我们还发现，氟伐他汀可增强Erastin、RSL-3等诱导的ferroptosis；裸鼠模型中抑制ferroptosis，可显著削弱氟伐他汀的抗骨转移功能。本项目我们拟在体外、体内研究氟伐他汀调节ferroptosis的功能和分子机制，明确ferroptosis在氟伐他汀抗骨转移中的作用，并研究氟伐他汀介导的 ferroptosis是否对高耐药间质型肿瘤细胞具杀伤作用；此外，我们将阐明氟伐他汀诱导的自噬和ferroptosis间的交互调控关系，及氟伐他汀联合自噬、ferroptosis激活剂在抗骨转移治疗中的应用。本研究将为肺腺癌骨转移治疗提供新的思路和手段。

Bone metastasis is one of the most frequent complications for lung cancer. Current anti-bone metastasis medications have lots defects, so finding new high-efficient and low toxic anti-bone metastasis treatments is an urgent need in current medical research. We revealed that fluvastatin can trigger autophagy in lung adenocarcinoma and suppress the cancer cells bone metastasis in autophay-dependent manner. Recently, we further found that fluvastatin can enhance ferroptosis induced by Erastin and RSL-3. Nude mice model showed that suppression of ferroptosis can significantly attenuate fluvastatin-mediated anti-bone metastasis activity. In this project, we intend to further study the role and molecular mechanisms of fluvastatin in regulating ferroptosis in vitro and in vivo, and to clarify the role of ferroptosis in fluvastatin-mediated anti-bone metastasis. In addition, we will investigate the potential role of fluvastatin in killing the multi-drug resistant mesenchymal tumor cells. Moreover, we will clarify the relationship between autophagy and ferroptosis elicited by fluvastatin, and explore the fluvastatin-based anti-bone metastasis therapy in combination with autophagy inducers or/and ferroptosis inducers. This study may help to provide a new thought and method for the treatment of bone metastasis of lung adenocarcinoma.