Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples. SIGNIFICANCE Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia. This article is highlighted in the In This Issue feature, p. 587.

中文翻译：

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线粒体铁的药理学还原触发非典型的 BAX/BAK 依赖性细胞死亡。


人们越来越认识到癌细胞代谢提供了令人兴奋的治疗机会。然而，直接将代谢依赖性靶向与癌细胞细胞死亡诱导结合起来的药物在很大程度上仍然难以捉摸。在这里，我们报告了类似药物的小分子铁霉素降低了线粒体铁负荷，从而导致线粒体代谢的有效破坏。铁霉素促进 BAX/BAK 的募集和激活，但由此产生的线粒体外膜透化 (MOMP) 不会导致凋亡半胱天冬酶的有效激活，也不会通过抑制先前建立的程序性细胞死亡途径来阻止随后的细胞死亡。与铁霉素和 BH3 模拟物通过独立的非冗余途径诱导 MOMP 的事实相一致，我们发现铁霉素在体外和体内与维奈托克表现出显着的协同作用，并克服了主要患者样本中的维奈托克耐药性。意义 铁霉素通过减少线粒体铁，将细胞代谢靶向与细胞死亡结合起来，从而导致线粒体代谢的改变和 BAX/BAK 的激活。铁霉素通过与 BH3 模拟物不同的机制诱导 MOMP，因此联合治疗在急性髓系白血病等癌症中具有显着的协同作用。本文在本期专题第 12 页中重点介绍。 587.