基于RBBP4介导的自噬性死亡研究雷公藤甲素抗非小细胞肺癌的作用机制

非小细胞肺癌是临床高发的恶性肿瘤之一，至今仍缺乏有效的治疗手段。RBBP4作为维持染色质结构稳定的重要蛋白，在非小细胞肺癌组织中高表达，下调RBBP4可诱导DNA损伤，而DNA损伤可通过激活cGAS-STING信号通路诱导细胞自噬性死亡。申请人前期研究表明雷公藤甲素可显著下调肺癌细胞中RBBP4表达，并通过诱导自噬性死亡抑制肺癌细胞，其潜在机制为雷公藤下调RBBP4表达诱导DNA损伤从而激活cGAS-STING信号通路，并进一步导致肺癌细胞发生自噬性死亡。因此，本项目拟通过回顾性研究RBBP4与非小细胞肺癌的临床相关性和预后价值，并采用单细胞凝胶电泳、激光共聚焦和原位移植瘤等实验手段在细胞和动物水平阐明雷公藤甲素调控RBBP4表达诱导肺癌细胞自噬性死亡的分子机制。项目研究将为诠释中药活性成分抗肿瘤分子机制提供科学依据，并为发展以RBBP4为靶点的非小细胞肺癌治疗方法提供新思路。

Non-small cell lung cancer (NSCLC) is one of the most malignant tumors with high morbidity, and there is still no effective therapy to cure it. RBBP4, as an important protein to maintain the stability of chromatin structure, is highly expressed in NSCLC tissues, and down-regulation of RBBP4 can induce DNA damage, and DNA damage induces autophagic cell death through the cGAS-STING signal axis. The applicant preliminarily found that triptolide significantly down-regulated RBBP4 expression in NSCLC cells, and suppress lung cancer cells by inducing autophagic cell death, its potential mechanism is to down-regulate RBBP4 expression and induce DNA damage to activate the cGAS-STING signal axis, further cause autophagic cell death in NSCLC cells. The molecular mechanism of triptolide regulating RBBP4 expression and inducing autophagic cell death will be elucidated by retrospectively analysing the clinical relevance and prognostic value of RBBP4 in non-small cell lung cancer, and by using single-cell gel electrophoresis, laser confocal and orthotopic aninal model, etc. The research will provide scientific basis for elucidating the antitumor molecular mechanism of active ingredient from Chinese herbs, and provide ideas for developing new NSCLC therapy by targeting RBBP4.