肿瘤低氧促进了胶质母细胞瘤的恶性进展和治疗抵抗性，部分原因是增加了过氧化氢（H2O2）的产生，这是一种细胞代谢反应关键的活性氧物质，同时还作为第二信使发挥额外作用。然而，在低氧的胶质母细胞瘤中，防止H2O2过载和随后肿瘤细胞损伤的分解途径仍然不清楚。在这里，我们提出了一个低氧协调型H2O2调节机制，其中通过低氧诱导因子1α（HIF-1α）与谷胱甘肽过氧化酶1（GPx1）启动子的结合，降低了低氧诱导生成的过量H2O2，GPx1是一种抗氧化酶，可以排除H2O2。GPx1耗竭会导致胶质母细胞瘤细胞中H2O2的过载和凋亡，以及胶质母细胞瘤裸鼠移植瘤的生长抑制。此外，肿瘤低氧也会增加外泌体GPx1的表达，该GPx1协助胶质母细胞瘤和内皮细胞在体外和体内阻止H2O2或辐射引起的凋亡。临床数据进一步表明，GPx1的表达与肿瘤等级、HIF-1α的表达、HIF-1α靶基因及外泌体标记基因的表达呈正相关；相反，它与人胶质母细胞瘤样本的总生存率呈负相关。我们的分析验证了低氧胶质母细胞瘤中H2O2的氧化还原平衡与临床相关，并且可以由HIF-1α促进或外泌体相关的GPx1维持。版权所有 © 2023. Elsevier B.V. 发布

Tumor hypoxia promotes malignant progression and therapeutic resistance in glioblastoma partly by increasing the production of hydrogen peroxide (H2O2), a type of reactive oxygen species critical for cell metabolic responses due to its additional role as a second messenger. However, the catabolic pathways that prevent H2O2 overload and subsequent tumor cell damage in hypoxic glioblastoma remain unclear. Herein, we present a hypoxia-coordinated H2O2 regulatory mechanism whereby excess H2O2 in glioblastoma induced by hypoxia is diminished by glutathione peroxidase 1 (GPx1), an antioxidant enzyme detoxifying H2O2, via the binding of hypoxia-inducible factor-1α (HIF-1α) to GPx1 promoter. Depletion of GPx1 results in H2O2 overload and apoptosis in glioblastoma cells, as well as growth inhibition in glioblastoma xenografts. Moreover, tumor hypoxia increases exosomal GPx1 expression, which assists glioblastoma and endothelial cells in countering H2O2 or radiation-induced apoptosis in vitro and in vivo. Clinical data explorations further demonstrate that GPx1 expression was positively correlated with tumor grade and expression of HIF-1α, HIF-1α target genes, and exosomal marker genes; by contrast, it was inversely correlated with the overall survival outcome in human glioblastoma specimens. Our analyses validate that the redox balance of H2O2 within hypoxic glioblastoma is clinically relevant and could be maintained by HIF-1α-promoted or exosome-related GPx1.Copyright © 2023. Published by Elsevier B.V.