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 突变的胶质瘤中的谷胱甘肽代谢

编码异柠檬酸脱氢酶 (IDH) 1 和 2 的基因突变是常见的癌症相关遗传异常。具有突变 IDH 的恶性肿瘤表现出相似的发病机制、代谢模式和耐药特征。然而，针对 IDH1 突变的实体瘤的有效疗法仍然不可用。在这项研究中，我们发现 IDH1 突变的获得会导致 NADP+/NADPH 平衡的破坏和对谷胱甘肽 (GSH) 代谢的需求增加。此外，核因子红细胞 2 相关因子 2 (Nrf2) 通过促进 GSH 合成和活性氧清除，在 IDH1 突变细胞中发挥关键保护作用。通过 brusatol 给药对 Nrf2/GSH 通路的药理学抑制在体外和体内对 IDH1 突变的癌症表现出有效的肿瘤抑制作用。