Mutations in genes encoding isocitrate dehydrogenases (IDH) 1 and 2 are common cancer-related genetic abnormalities. Malignancies with mutated IDHs exhibit similar pathogenesis, metabolic pattern, and resistance signature. However, an effective therapy against IDH1-mutated solid tumor remains unavailable. In this study, we showed that acquisition of IDH1 mutation results in the disruption of NADP+/NADPH balance and an increased demand for glutathione (GSH) metabolism. Moreover, the nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key protective role in IDH1-mutated cells by prompting GSH synthesis and reactive oxygen species scavenging. Pharmacologic inhibition of the Nrf2/GSH pathway via brusatol administration exhibited a potent tumor suppressive effect on IDH1-mutated cancer in vitro and in vivo Our findings highlight a possible therapeutic strategy that could be valuable for IDH1-mutated cancer treatment.

中文翻译：

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阻断IDH1突变脑胶质瘤中谷胱甘肽的代谢。

编码异柠檬酸脱氢酶（IDH）1和2的基因突变是常见的与癌症相关的遗传异常。IDHs突变的恶性肿瘤表现出相似的发病机制，代谢模式和耐药性特征。但是，仍然没有针对IDH1突变的实体瘤的有效疗法。在这项研究中，我们表明获得IDH1突变会导致NADP + / NADPH平衡的破坏和对谷胱甘肽（GSH）代谢的需求增加。此外，通过促进GSH合成和清除活性氧，核因子类红细胞2相关因子2（Nrf2）在IDH1突变的细胞中起着重要的保护作用。