Glioblastomas（GBMs）表现出明显的代谢失调以促进肿瘤生长。而 glioblastoma 干细胞(GSCs)适应于异质性营养供应区，但仍然显示对新生胆固醇合成的依赖性。转录因子Sterol Regulatory Element-Binding Protein 2 (SREBP2)调节胆固醇合成酶和摄取受体。在这里，我们研究了 GSCs在不同胆固醇供应下的适应行为。患者肿瘤的体外分析显示胆固醇合成与血管生成的降低有关。对于匹配的 GBM 标本和 GSCs 进行了胆固醇合成酶的比较基因表达。进行了体外和体内失去功能的遗传学和药理学测定，以评估 SREBP2 对 GBM 胆固醇合成，增殖和自我更新的影响。利用 ChIP-qPCR 来绘制 SREBP2 对 GSCs 的胆固醇合成酶和摄取受体的调控。胆固醇合成酶在 GBM 肿瘤核心的表达水平高于侵袭性边缘。SREBP2 促进 GSCs 的胆固醇合成，尤其是在饥饿情况下，以及促进增殖、自我更新和肿瘤生长。在不同营养条件下，SREBP2 控制胆固醇合成和摄取的平衡。SREBP2在微环境中的可用性基础上显示出特定胆固醇生物学的调控，该调控在肿瘤核心中诱导胆固醇合成并在边缘中诱导摄取，为 GBM 提供了一种新的治疗策略。©2023年作者（们）。由牛津大学出版社代表 Society for Neuro-Oncology 发布。保留所有权利。要获得许可，请发送电子邮件至：journals.permissions@oup.com。

Glioblastomas (GBMs) display striking dysregulation of metabolism to promote tumor growth. Glioblastoma stem cells (GSCs) adapt to regions of heterogeneous nutrient availability, yet display dependency on de novo cholesterol biosynthesis. The transcription factor Sterol Regulatory Element-Binding Protein 2 (SREBP2) regulates cholesterol biosynthesis enzymes and uptake receptor. Here, we investigate adaptive behavior of GSCs under different cholesterol supplies.In silico analysis of patient tumors demonstrated enrichment of cholesterol synthesis associated with decreased angiogenesis. Comparative gene expression of cholesterol biosynthesis enzymes in paired GBM specimens and GSCs were performed. In vitro and in vivo loss-of-function genetic and pharmacologic assays were conducted to evaluate the effect of SREBP2 on GBM cholesterol biosynthesis, proliferation, and self-renewal. ChIP-qPCR was leveraged to map the regulation of SREBP2 to cholesterol biosynthesis enzymes and uptake receptor in GSCs.Cholesterol biosynthetic enzymes were expressed at higher levels in GBM tumor cores than invasive margins. SREBP2 promoted cholesterol biosynthesis in GSCs, especially under starvation, as well as proliferation, self-renewal, and tumor growth. SREBP2 governed the balance between cholesterol biosynthesis and uptake in different nutrient condition.SREBP2 displays context-specific regulation of cholesterol biology based on its availability in the microenvironment with induction of cholesterol biosynthesis in the tumor core and uptake in the margin, informing a novel treatment strategy for GBM.© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.