代谢重编程通过为高度增殖的肿瘤细胞产生足够的能量，在胶质母细胞瘤（GBM）的进展和复发中发挥着至关重要的作用。此外，代谢重编程对于肿瘤生长和免疫逃逸机制至关重要。 GBM 细胞中经常检测到表皮生长因子受体 (EGFR) 扩增和 EGFR-vIII 突变，从而导致恶性行为。本研究旨在探讨EGFR通路在脂肪酸代谢重塑和能量产生中的功能作用。选择临床GBM标本进行单细胞RNA测序和非靶向代谢组学分析。构建并验证了代谢相关的 RTK 脂肪酸基因特征。 MK-2206和MK-803用于阻断RTK途径和甲羟戊酸途径诱导的异常代谢。监测具有激活 EGFR 通路的 GBM 的能量代谢。通过体内颅内肿瘤模型分析替莫唑胺（TMZ）辅助的奥希替尼和阿托伐他汀的抗肿瘤作用。单细胞RNA测序和代谢组学支持高EGFR表达的GBM具有脂质重塑和维持高胆固醇水平的特征。临床 GBM 样本。抑制 EGFR/AKT 和甲羟戊酸途径可以通过抑制三羧酸循环和调节 ATP 产生来重塑能量代谢。从机制上讲，EGFR/AKT通路上调酰基辅酶A合成酶短链家族成员3（ACSS3）、酰基辅酶A合成酶长链家族成员3（ACSL3）和长链脂肪酸延伸相关基因ELOVL的表达脂肪酸延长酶 2 (ELOVL2) 以 NF-κB 依赖性方式发挥作用。此外，甲羟戊酸途径的抑制降低了细胞膜上的EGFR水平，从而影响EGFR/AKT途径的信号转导。因此，针对EGFR/AKT和甲羟戊酸通路增强了TMZ在GBM细胞和动物模型中的抗肿瘤作用。我们的研究结果不仅揭示了EGFR激活的GBM中代谢重编程的机制，而且为临床GBM管理提供了组合治疗策略。 © 2023 作者。约翰·威利出版的《癌症通讯》

Metabolism reprogramming plays a vital role in glioblastoma (GBM) progression and recurrence by producing enough energy for highly proliferating tumor cells. In addition, metabolic reprogramming is crucial for tumor growth and immune-escape mechanisms. Epidermal growth factor receptor (EGFR) amplification and EGFR-vIII mutation are often detected in GBM cells, contributing to the malignant behavior. This study aimed to investigate the functional role of the EGFR pathway on fatty acid metabolism remodeling and energy generation.Clinical GBM specimens were selected for single-cell RNA sequencing and untargeted metabolomics analysis. A metabolism-associated RTK-fatty acid-gene signature was constructed and verified. MK-2206 and MK-803 were utilized to block the RTK pathway and mevalonate pathway induced abnormal metabolism. Energy metabolism in GBM with activated EGFR pathway was monitored. The antitumor effect of Osimertinib and Atorvastatin assisted by temozolomide (TMZ) was analyzed by an intracranial tumor model in vivo.GBM with high EGFR expression had characteristics of lipid remodeling and maintaining high cholesterol levels, supported by the single-cell RNA sequencing and metabolomics of clinical GBM samples. Inhibition of the EGFR/AKT and mevalonate pathways could remodel energy metabolism by repressing the tricarboxylic acid cycle and modulating ATP production. Mechanistically, the EGFR/AKT pathway upregulated the expressions of acyl-CoA synthetase short-chain family member 3 (ACSS3), acyl-CoA synthetase long-chain family member 3 (ACSL3), and long-chain fatty acid elongation-related gene ELOVL fatty acid elongase 2 (ELOVL2) in an NF-κB-dependent manner. Moreover, inhibition of the mevalonate pathway reduced the EGFR level on the cell membranes, thereby affecting the signal transduction of the EGFR/AKT pathway. Therefore, targeting the EGFR/AKT and mevalonate pathways enhanced the antitumor effect of TMZ in GBM cells and animal models.Our findings not only uncovered the mechanism of metabolic reprogramming in EGFR-activated GBM but also provided a combinatorial therapeutic strategy for clinical GBM management.© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.