自然化合物青蒿素是全球广泛使用的最常用的抗疟疾药物，基于其细胞毒性，还可用于抗癌治疗。青蒿素及其衍生物是内过氧化物，在真核细胞中破坏蛋白质；然而，它们的确切作用机制和靶细胞仍然大多数不清楚。通过使用酵母和单倍体干细胞筛选，我们证明单一细胞途径，即卟啉（血红素）生物合成途径，是青蒿素细胞毒性所必需的。遗传或药理学上调节卟啉生产足以改变其在真核细胞中的细胞毒性。使用多个人脑肿瘤发展模型，例如大脑胶质母细胞瘤器官样体和患者源性肿瘤球，我们使用经临床批准的卟啉增强剂和手术荧光标记5-氨基乙酰丙酸（5-ALA）增强脱氢青蒿素对癌细胞的敏感性。青蒿素和5-ALA的联合治疗显着且特异性地杀死了所有模型系统中的脑肿瘤细胞，包括体内同种异基移植的患者源性异种移植物。这些数据揭示了青蒿素细胞毒性的关键分子途径和一种敏感化策略，用于治疗不同的脑肿瘤，包括药物耐药性人类胶质母细胞瘤。© 2023年作者。根据CC BY 4.0许可证条款出版。

The natural compound Artemisinin is the most widely used antimalarial drug worldwide. Based on its cytotoxicity, it is also used for anticancer therapy. Artemisinin and its derivates are endoperoxides that damage proteins in eukaryotic cells; their definite mechanism of action and host cell targets, however, have remained largely elusive. Using yeast and haploid stem cell screening, we demonstrate that a single cellular pathway, namely porphyrin (heme) biosynthesis, is required for the cytotoxicity of Artemisinins. Genetic or pharmacological modulation of porphyrin production is sufficient to alter its cytotoxicity in eukaryotic cells. Using multiple model systems of human brain tumor development, such as cerebral glioblastoma organoids, and patient-derived tumor spheroids, we sensitize cancer cells to dihydroartemisinin using the clinically approved porphyrin enhancer and surgical fluorescence marker 5-aminolevulinic acid, 5-ALA. A combination treatment of Artemisinins and 5-ALA markedly and specifically killed brain tumor cells in all model systems tested, including orthotopic patient-derived xenografts in vivo. These data uncover the critical molecular pathway for Artemisinin cytotoxicity and a sensitization strategy to treat different brain tumors, including drug-resistant human glioblastomas.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.