Glioblastoma (GBM), a mostly lethal brain tumor, acquires large amounts of free fatty acids (FAs) to promote cell growth. But how the cancer avoids lipotoxicity is unknown. Here, we identify that GBM upregulates diacylglycerol-acyltransferase 1 (DGAT1) to store excess FAs into triglycerides and lipid droplets. Inhibiting DGAT1 disrupted lipid homeostasis and resulted in excessive FAs moving into mitochondria for oxidation, leading to the generation of high levels of reactive oxygen species (ROS), mitochondrial damage, cytochrome c release, and apoptosis. Adding N-acetyl-cysteine or inhibiting FA shuttling into mitochondria decreased ROS and cell death induced by DGAT1 inhibition. We show in xenograft models that targeting DGAT1 blocked lipid droplet formation, induced tumor cell apoptosis, and markedly suppressed GBM growth. Together, our study demonstrates that DGAT1 upregulation protects GBM from oxidative damage and maintains lipid homeostasis by facilitating storage of excess FAs. Targeting DGAT1 could be a promising therapeutic approach for GBM.

胶质母细胞瘤 (GBM) 是一种主要致命的脑肿瘤，它获得大量游离脂肪酸 (FA) 以促进细胞生长。但癌症如何避免脂毒性尚不清楚。在这里，我们确定 GBM 上调二酰基甘油酰基转移酶 1 (DGAT1) 以将过量的 FA 储存到甘油三酯和脂滴中。抑制 DGAT1 会破坏脂质稳态，导致过多的 FA 进入线粒体进行氧化，导致产生高水平的活性氧 (ROS)、线粒体损伤、细胞色素c释放和凋亡。添加 N-乙酰半胱氨酸或抑制 FA 穿梭进入线粒体可减少 DGAT1 抑制诱导的 ROS 和细胞死亡。我们在异种移植模型中显示，靶向 DGAT1 可阻止脂滴形成，诱导肿瘤细胞凋亡，并显着抑制 GBM 生长。总之，我们的研究表明，DGAT1 上调可保护 GBM 免受氧化损伤，并通过促进过量 FA 的储存来维持脂质稳态。靶向 DGAT1 可能是一种很有前景的 GBM 治疗方法。