胶质母细胞瘤（GBM）是中枢神经系统中最具恶性和预后最差的脑肿瘤。线粒体代谢在癌症的发生和发展中发挥着重要的作用，为肿瘤合成提供关键物质。Mito-LND是一种新型的小分子抑制剂，可以选择性地抑制肿瘤细胞的能量代谢。然而，Mito-LND在GBM的治疗效果尚不清楚。本研究评估了Mito-LND对GBM细胞生长的抑制作用，并阐明了其潜在机制。结果显示，Mito-LND能抑制GBM细胞的存活、增殖和形成集落。此外，Mito-LND还导致细胞周期停滞和凋亡。从机制上讲，Mito-LND抑制线粒体呼吸链复合物I的活性，降低线粒体膜电势，从而促进ROS产生。重要的是，Mito-LND通过阻断Raf/MEK/ERK信号通路来抑制GBM的恶性增殖。体内实验显示，Mito-LND抑制小鼠GBM异种移植瘤的生长，并显著延长了带瘤小鼠的生存时间。总的来说，当前发现支持以线粒体代谢为靶点可能是GBM治疗的潜在和有前景的策略，这将为进一步的Mito-LND临床试验奠定理论基础。© 2023. BioMed Central Ltd., part of Springer Nature.

Glioblastoma (GBM) is a brain tumor with the highest level of malignancy and the worst prognosis in the central nervous system. Mitochondrial metabolism plays a vital role in the occurrence and development of cancer, which provides critical substances to support tumor anabolism. Mito-LND is a novel small-molecule inhibitor that can selectively inhibit the energy metabolism of tumor cells. However, the therapeutic effect of Mito-LND on GBM remains unclear.The present study evaluated the inhibitory effect of Mito-LND on the growth of GBM cells and elucidated its potential mechanism.The results showed that Mito-LND could inhibit the survival, proliferation and colony formation of GBM cells. Moreover, Mito-LND induced cell cycle arrest and apoptosis. Mechanistically, Mito-LND inhibited the activity of mitochondrial respiratory chain complex I and reduced mitochondrial membrane potential, thus promoting ROS generation. Importantly, Mito-LND could inhibit the malignant proliferation of GBM by blocking the Raf/MEK/ERK signaling pathway. In vivo experiments showed that Mito-LND inhibited the growth of GBM xenografts in mice and significantly prolonged the survival time of tumor-bearing mice.Taken together, the current findings support that targeting mitochondrial metabolism may be as a potential and promising strategy for GBM therapy, which will lay the theoretical foundation for further clinical trials on Mito-LND in the future.© 2023. BioMed Central Ltd., part of Springer Nature.