胶质母细胞瘤被认为起源于脑室下神经干细胞(NSC)，这些细胞获得基因变异。在成年人的大脑中，NSC基本处于静止状态，这表明维持静止状态的非正常调节可能是肿瘤发生的先决条件。虽然抑癌基因p53的失活在胶质母细胞瘤形成过程中是一个常见事件，但是否和如何影响静止的NSC还不清楚。在这里，我们展示p53通过诱导脂肪酸氧化（FAO）来维持静止状态，而在静止NSC(qNSC)中急性p53敲除将导致它们提前到增殖状态。在机制上，这是通过直接转录诱导PPARGC1a而发生的，PPARGC1a进而激活PPARα来上调FAO基因。补充含有ω-3脂肪酸的鱼油，天然PPARα配体，可以完全恢复p53缺失NSC的静止状态，在胶质母细胞瘤小鼠模型中延迟肿瘤的发生。因此，饮食可以抑制胶质母细胞瘤的驱动基因突变，这对于癌症预防具有重要意义。版权所有©2023作者。Elsevier Inc.保留所有权利。

Glioblastoma is thought to originate from neural stem cells (NSCs) of the subventricular zone that acquire genetic alterations. In the adult brain, NSCs are largely quiescent, suggesting that deregulation of quiescence maintenance may be a prerequisite for tumor initiation. Although inactivation of the tumor suppressor p53 is a frequent event in gliomagenesis, whether or how it affects quiescent NSCs (qNSCs) remains unclear. Here, we show that p53 maintains quiescence by inducing fatty-acid oxidation (FAO) and that acute p53 deletion in qNSCs results in their premature activation to a proliferative state. Mechanistically, this occurs through direct transcriptional induction of PPARGC1a, which in turn activates PPARα to upregulate FAO genes. Dietary supplementation with fish oil containing omega-3 fatty acids, natural PPARα ligands, fully restores quiescence of p53-deficient NSCs and delays tumor initiation in a glioblastoma mouse model. Thus, diet can silence glioblastoma driver mutations, with important implications for cancer prevention.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.