诱导替代性非凋亡细胞死亡程序（例如细胞致死性自噬和线粒体自噬）代表了对抗胶质母细胞瘤（GBM）的可能策略。在此，我们报道 VLX600 是一种新型铁螯合剂和氧化磷酸化 (OXPHOS) 抑制剂，可诱导不依赖半胱天冬酶的细胞死亡，这种死亡在贴壁 U251 ATG5/7（自噬相关 5/7）敲除 (KO) GBM 细胞中得到部分挽救和 NCH644 ATG5/7 敲低 (KD) 神经胶质瘤干样细胞 (GSC)，表明 VLX600 在 GBM 中诱导自噬依赖性细胞死亡 (ADCD)。这种 ADCD 伴随着耗氧量减少、BNIP3（BCL2 相互作用蛋白 3）和 BNIP3L（BCL2 相互作用蛋白 3 样）表达/线粒体定位增加、线粒体标记蛋白（例如 COX4I1（细胞色素）水平降低）诱导线粒体自噬。 c 氧化酶亚基 4I1)) 和 mitoKeima 测定以及组蛋白 H3 和 H4 赖氨酸三甲基化增加。此外，细胞外添加铁能够显着挽救 VLX600 诱导的细胞死亡和线粒体自噬，表明铁代谢对于 GBM 细胞稳态的重要作用。有趣的是，VLX600还能够在器官型脑切片移植模型中完全消除NCH644 GSC肿瘤。我们的数据支持 GBM 中 ADCD 诱导的治疗概念，并表明 VLX600 可能是治疗该肿瘤的有趣的新型候选药物。

Induction of alternative, non-apoptotic cell death programs such as cell-lethal autophagy and mitophagy represent possible strategies to combat glioblastoma (GBM). Here we report that VLX600, a novel iron chelator and oxidative phosphorylation (OXPHOS) inhibitor, induces a caspase-independent type of cell death that is partially rescued in adherent U251 ATG5/7 (autophagy related 5/7) knockout (KO) GBM cells and NCH644 ATG5/7 knockdown (KD) glioma stem-like cells (GSCs), suggesting that VLX600 induces an autophagy-dependent cell death (ADCD) in GBM. This ADCD is accompanied by decreased oxygen consumption, increased expression/mitochondrial localization of BNIP3 (BCL2 interacting protein 3) and BNIP3L (BCL2 interacting protein 3 like), the induction of mitophagy as demonstrated by diminished levels of mitochondrial marker proteins (e.g. COX4I1 (cytochrome c oxidase subunit 4I1)) and the mitoKeima assay as well as increased histone H3 and H4 lysine tri-methylation. Further, the extracellular addition of iron is able to significantly rescue VLX600-induced cell death and mitophagy, pointing out an important role of iron metabolism for GBM cell homeostasis. Interestingly, VLX600 is also able to completely eliminate NCH644 GSC tumors in an organotypic brain slice transplantation model. Our data support the therapeutic concept of ADCD induction in GBM and suggest that VLX600 may be an interesting novel drug candidate for the treatment of this tumor.