癌症治疗的一种潜在治疗方法是同时靶向氧化磷酸化和糖酵解。水泡性口炎病毒（VSV MP）的基质蛋白可以靶向线粒体表面，引起可能与线粒体功能障碍和氧化磷酸化抑制相关的形态变化。先前的研究表明，线粒体异常可以将葡萄糖代谢引导至糖酵解。因此，用VSV MP治疗后，糖酵解抑制对于完全阻断葡萄糖代谢和根除癌症是必要的。为了抑制糖酵解，2-脱氧-D-葡萄糖 (2-DG)（一种合成葡萄糖类似物）被用来与 VSV MP 结合来治疗癌症。本研究旨在确定 VSV MP 如何影响癌细胞的葡萄糖生物能代谢，并评估 2-DG 与 VSV 联合使用时的协同效应。我们的结果表明，在 U87 和 C6 胶质母细胞瘤细胞系中，VSV MP 导致线粒体膜电位损失、细胞色素 c 释放和葡萄糖生物能代谢重编程。当与 2-DG 联合使用时，VSV MP 会协同加重细胞活力、细胞凋亡和 G2/M 期阻滞。同时，联合疗法加剧了 ATP 消耗，激活 AMPK，并抑制 mTOR 信号通路。此外，单独的2-DG治疗诱导胶质母细胞瘤细胞自噬，然而，VSV MP抑制联合治疗中2-DG诱导的自噬，最终有助于联合策略增强U87和C6癌细胞的细胞毒作用。在原位 U87 胶质母细胞瘤模型和皮下 C6 胶质母细胞瘤模型中，联合治疗导致肿瘤显着消退并延长了生存期。 VSV MP 和糖酵解抑制剂的组合可能是治疗胶质母细胞瘤的有效治疗方法。

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism towards glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog, was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP effects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mTOR signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells, however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment, and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.