铁死亡是一种由铁依赖的脂质过氧化诱导的调节性细胞死亡。血红素应答转录因子BTB和CNC同源1（BACH1）通过抑制参与谷胱甘肽（GSH）合成和细胞内不稳定铁代谢的基因转录来促进铁死亡，这是铁死亡的关键调节通路。我们发现，在没有任何铁死亡诱导剂的情况下，BACH1重新表达可以在去除2-巯基乙醇后诱导Bach1-/-不朽小鼠胚胎成纤维细胞（iMEFs）中的铁死亡。在这些iMEFs中，GSH合成减少，而细胞内不稳定铁水平增高。我们利用该系统研究主要的铁死亡调节因子谷胱甘肽过氧化物酶4（Gpx4）和线粒体相关的凋亡诱导因子2（Aifm2）以及铁死亡抑制蛋白1基因是否是BACH1的靶基因。在iMEFs中，Gpx4和Aifm2均未受BACH1调控。然而，我们发现BACH1在人胰腺癌细胞中抑制AIFM2转录。这些结果表明，BACH1针对铁死亡的调节因子可能在不同的细胞类型和动物物种中各异。此外，我们证实了BACH1重新表达诱导的铁死亡具有传播效应。BACH1重新表达代表一种在GPX4或系统Xc-抑制后诱导铁死亡的新策略，并有望为未来的铁死亡研究做出贡献。© 作者（2023）。由牛津大学出版社代表日本生化学会出版。保留所有权利。

Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation. The heme-responsive transcription factor BTB and CNC homology 1 (BACH1) promotes ferroptosis by repressing the transcription of genes involved in glutathione (GSH) synthesis and intracellular labile iron metabolism, which are key regulatory pathways in ferroptosis. We found that BACH1 re-expression in Bach1-/- immortalized mouse embryonic fibroblasts (iMEFs) can induce ferroptosis upon 2-mercaptoethanol removal, without any ferroptosis inducers. In these iMEFs, GSH synthesis was reduced, and intracellular labile iron levels were increased upon BACH1 re-expression. We used this system to investigate whether the major ferroptosis regulators glutathione peroxidase 4 (Gpx4) and apoptosis-inducing factor mitochondria-associated 2 (Aifm2), the gene for ferroptosis suppressor protein 1, are target genes of BACH1. Neither Gpx4 nor Aifm2 was regulated by BACH1 in the iMEFs. However, we found that BACH1 represses AIFM2 transcription in human pancreatic cancer cells. These results suggest that the ferroptosis regulators targeted by BACH1 may vary across different cell types and animal species. Furthermore, we confirmed that the ferroptosis induced by BACH1 re-expression exhibited a propagating effect. BACH1 re-expression represents a new strategy for inducing ferroptosis after GPX4 or system Xc- suppression, and is expected to contribute to future ferroptosis research.© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.