自噬是一种重要的细胞应激反应机制，癌细胞常常利用它来在营养缺乏和缺氧等压力下维持迅速生长。自噬在肿瘤对化疗、放疗或靶向治疗的抗药性中也起着关键作用。因此，抑制自噬是一种有前途的肿瘤治疗策略。然而，当前缺乏适合临床使用的有效自噬抑制剂。大多数药物研发都集中在酶类，如VPS34和ULK1激酶，或在自噬中发挥不同作用的半胱氨酸蛋白酶ATG4B上。我们发现了一种药物分子Eltrombopag，它通过直接抑制转录因子EB (TFEB) 来抑制自噬溶酶体基因的表达，在这一阶段，这些蛋白质的合成并没有真正开始。这种药物可以改善Temozolomide对脑胶质母细胞瘤的治疗效果，进一步证实了抑制自噬在癌症治疗中的价值。缩写：VPS34：液泡蛋白分类34；ULK1：类似于unc-51的自噬激活激酶1；TFEB：转录因子EB；MITF：与小眼病相关的转录因子；TFE3：转录因子E3；EO：Eltrombopag；ITC：等温滴定量热法；bHLH-LZ：碱性螺旋-环-螺旋-亮氨酸基因家族；LAMP1：溶酶体相关膜蛋白1；CTSF：半胱氨酸蛋白酶F；HEXA：N-乙酰神经氨酸酰基酶亚基α。

Autophagy, an important cellular stress response mechanism, is often exploited by a variety of cancer cells to sustain rapid growth under stresses such as nutrient deprivation and hypoxia. Autophagy also plays a key role in tumor resistance to chemotherapy, radiotherapy or targeted therapy. Inhibition of autophagy is therefore a promising tumor treatment strategy. However, there is still a lack of effective autophagy inhibitors suitable for clinical use. Most drug development has focused on enzymes like the VPS34 and ULK1 kinases, or the cysteine protease ATG4B, which plays different roles in autophagy. We discovered a drug molecule Eltrombopag that inhibits the expression of autophagic lysosomal genes at the stage of transcriptional level, where the synthesis of these proteins has not really begun, by directly inhibiting the TFEB (transcription factor EB). This drug can improve the therapeutic effect of Temozolomide on glioblastoma treatment, further confirming the value of inhibiting autophagy in the treatment of cancer.Abbreviation: VPS34: vacuolar protein sorting 34; ULK1: unc-51 like autophagy activating kinase 1; TFEB: transcription factor EB; MITF: microphthalmia-associated transcription factor; TFE3: transcription factor E3; EO: Eltrombopag; ITC: isothermal titration calorimetry; bHLH-LZ: basic helix-loop-helix leucine zipper; LAMP1: lysosomal-associated membrane protein 1; CTSF: cathepsin F; HEXA: hexosaminidase subunit alpha.