自噬对脑胶质瘤发生发展及替莫唑胺（TMZ）敏感性起着重要调控作用，但机制尚不明确。利用数据挖掘发现ATG4C基因是胶质瘤患者预后的独立危险因素；动物及细胞实验表明干扰ATG4C表达可抑制裸鼠体内成瘤，促进凋亡，抑制自噬流，增加ROS释放量及自噬蛋白LCII 、P62表达，加入TMZ自噬及胶质瘤细胞活力均受到抑制。进一步的生物信息挖掘和文献查阅提示ATG4C可能通过影响GABARAP家族蛋白的功能，以及通过GABARAP/Nix介导的线粒体自噬，经ROS介导的溶酶体pH值改变而间接抑制自噬体-溶酶体融合，调控机制促进TMZ的敏感性介导TMZ敏感性。本项目拟在临床、动物及分子机制上联合运用流式技术，活细胞荧光显微检测技术，电镜观察自噬体及自噬溶酶体，免疫共沉淀等方法系统研究ATG4C调控自噬体和溶酶体融合影响TMZ敏感性分子机制。

Autophagy plays an important role in temozolomide (TMZ) chemotherapy resistance on glioma, but the underlying mechanism remains unclear yet. Data mining showed that ATG4C was an independent risk factor for the prognosis of glioma patients. Our results showed that ATG4C knockdown inhibited glioma growth,suppressed autophagy flow, then promoted ROS production and the expression of autophagy proteins LCII and P62.Additionally, ATG4C ablation significantly inhibited TMZ-activated autophagy and increased TMZ chemosensitivity.The String database indicated that ATG4C might interact with GABARAP family proteins, which could regulate mitophagy by binding Nix on the mitochondrial membrane to produce ROS.And ROS may change lysosomal pH value, which regulates the late autophagosome-lysosome fusion and mediate the TMZ sensitivity. This project aims to systematically investigate the effects of ATG4C on autophagosome-lysosome fusion and TMZ chemosensitivity and underlying mechanism by using flow cytometry technology, fluorescence live-cell imaging, electron microscopy, immunoprecipitation assay and so on. .