ROS-driven mitophagy arrest mediates the anti-glioblastoma activity of Molephantin

Mitophagy, the selective autophagic degradation of mitochondria, often acts as a pro-survival mechanism in tumor cells, including Glioblastoma (GBM), by clearing damaged mitochondria and mitigating oxidative stress. GBM is a highly aggressive brain tumor characterized by profound resistance to conventional therapies. Our recent study identified Molephantin (EM-5), a natural small molecule capable of crossing the blood-brain barrier, as a potent anti-GBM agent. Mechanistically, EM-5 triggers severe mitochondrial dysfunction and massive reactive oxygen species (ROS) production in GBM. Crucially, we discovered that EM-5 acts as a novel late-stage mitophagy inhibitor. It specifically blocks the fusion of mitophagosomes with lysosomes without affecting early autophagosome formation or lysosomal acidification. This ROS-driven fusion defect leads to the toxic accumulation of damaged mitochondria, thereby amplifying oxidative stress and driving GBM cells into apoptosis. Collectively, our work establishes that targeting late-stage mitophagy flux via ROS modulation is a valuable paradigm for the discovery and development of therapeutic agents against GBM.