高级别胶质瘤是成年人中最常见的浸润性原发性脑肿瘤，具有高侵袭性、侵略性和对治疗的耐药性，这突出了开发具有新机制的有效药物的需求。本研究的目的是在压力条件下揭示蛋白组学谱的变化，以确定人异柠檬酸脱氢酶（IDH）突变高级别胶质瘤抗癌作用中的预后生物标记和改变的凋亡通路。我们的实验方案首先是3D体外发育的神经长球模型，然后用相关浓度的农药混合物进行处理。此外，我们采用了无靶向蛋白质组学方法结合高分辨质谱技术，对被处理和未处理的神经长球之间的差异表达蛋白进行了比较分析。我们的分析揭示了大多数变化的蛋白质是胶质瘤发病机制中的关键成员，与细胞代谢、生物调节、结合、催化和结构活性有关，并与许多级联调控途径相关。我们的研究发现，四级星形胶质瘤促进了有大量钙离子流入涉及有丝分裂原活化蛋白激酶/细胞外信号调节激酶（MAPK1/ERK2）通路下游的过程。促性腺激素释放激素信号增强MAPK的活性，可能作为负反馈补偿调节因子。因此，我们的研究为有效的新治疗和诊断策略铺平了道路，以提高总体生存率。

High-grade gliomas represent the most common group of infiltrative primary brain tumors in adults associated with high invasiveness, agressivity, and resistance to therapy, which highlights the need to develop potent drugs with novel mechanisms of action. The aim of this study is to reveal changes in proteome profiles under stressful conditions to identify prognostic biomarkers and altered apoptogenic pathways involved in the anticancer action of human isocitrate dehydrogenase (IDH) mutant high-grade gliomas. Our protocol consists first of a 3D in vitro developing neurospheroid model and then treatment by a pesticide mixture at relevant concentrations. Furthermore, we adopted an untargeted proteomic-based approach with high-resolution mass spectrometry for a comparative analysis of the differentially expressed proteins between treated and nontreated spheroids. Our analysis revealed that the majority of altered proteins were key members in glioma pathogenesis, implicated in the cellular metabolism, biological regulation, binding, and catalytic and structural activity and linked to many cascading regulatory pathways. Our finding revealed that grade-IV astrocytomas promote the downstream of the mitogen-activated-protein-kinases/extracellular-signal-regulated kinase (MAPK1/ERK2) pathway involving massive calcium influx. The gonadotrophin-releasing-hormone signaling enhances MAKP activity and may serve as a negative feedback compensating regulator. Thus, our study can pave the way for effective new therapeutic and diagnostic strategies to improve the overall survival.