近日，澳大利亚彼得麦卡勒姆癌症中心教授Lev M. Kats及其课题组探明了抑制血红素生物合成触发急性髓性白血病的铜细胞增生。这一研究成果发表在2025年11月19日出版的国际学术期刊《细胞》上。
通过对小鼠模型、人类细胞系和原发性患者样本的综合分析，该研究组确定急性髓性白血病（AML）中新生血红素生物合成是一种选择性依赖。AML细胞，特别是白血病干细胞（LSCs）倾向于下调血红素生物合成酶（HBEs），从而促进其自我更新，从而支持了这种依赖性。抑制HBEs会引起线粒体复合体IV的崩溃，并失调铜伴侣系统，诱导铜中毒，这是一种由铜脂化蛋白低聚化引起的程序性细胞死亡。
此外，研究组确定了血红素生物合成的合成致死途径，包括糖酵解，这可以用于联合策略。总之，他们的工作揭示了一种血红素变阻器，它与AML的基因表达和药物敏感性有关，并暗示HBE抑制是铜变的触发因素。
据悉，在大多数哺乳动物细胞中，泛素代谢产物血红素具有多种酶和信号功能。
附：英文原文
Title: Inhibition of heme biosynthesis triggers cuproptosis in acute myeloid leukemia
Author: Alexander C. Lewis, Emily Gruber, Rheana Franich, Jessica Armstrong, Madison J. Kelly, Carlos M. Opazo, Yau C. Low, Léa Flippe, Kevin Wijanarko, Caitlin L. Rowe, Celeste H. Mawal, Alexandra Birrell, Joan So, Srimayee Vaidyanathan, Keziah Ting, Liana N. Semcesen, Karena Last, Ching-Seng Ang, Giovanna Pomilio, Fiona C. Brown, Andrew H. Wei, Jason A. Powell, Elizabeth S. Ng, Ann E. Frazier, Kate McArthur, Najoua Lalaoui, David A. Stroud, Kristin K. Brown, Ricky W. Johnstone, Lev M. Kats
Issue&Volume: 2025-11-19
Abstract: The ubiquitous metabolite heme has diverse enzymatic and signaling functions in most mammalian cells. Through integrated analyses of mouse models, human cell lines, and primary patient samples, we identify de novo heme biosynthesis as a selective dependency in acute myeloid leukemia (AML). The dependency is underpinned by a propensity of AML cells, and especially leukemic stem cells (LSCs), to downregulate heme biosynthesis enzymes (HBEs), which promotes their self-renewal. Inhibition of HBEs causes the collapse of mitochondrial Complex IV and dysregulates the copper-chaperone system, inducing cuproptosis, a form of programmed cell death brought about by the oligomerization of lipoylated proteins by copper. Moreover, we identify pathways that are synthetic lethal with heme biosynthesis, including glycolysis, which can be leveraged for combination strategies. Altogether, our work uncovers a heme rheostat that is connected to gene expression and drug sensitivity in AML and implicates HBE inhibition as a trigger of cuproptosis.
DOI: 10.1016/j.cell.2025.10.028
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01233-4