Ferroptosis is programmed by the coordinated regulation of glutathione and iron metabolism by BACH1
2019
Ferroptosisis an iron-dependent
programmed cell deathresulting from alterations of metabolic processes. However, its regulation and physiological significance remain to be elucidated. By analyzing transcriptional responses of murine embryonic fibroblasts exposed to the
ferroptosis-inducer erastin, we found that a set of genes related to oxidative stress protection was induced upon
ferroptosis. We further showed that the transcription factor BACH1 promoted
ferroptosisby repressing the expression of a subset of erastin-inducible genes involved in the synthesis of glutathione or metabolism of intracellular
labileiron, including
Gclm,
Gclc,
Slc7a11,
Hmox1,
Fth1, Ftl1, and Slc40a1. Compared with wild-type mice, Bach1-/- mice showed resistance to myocardial infarction, the seriousness of which was palliated by the
iron-chelator
deferasirox, which suppressed
ferroptosis. Our findings suggest that
ferroptosisis programmed at the transcriptional level to induce genes combating
labile-iron-induced oxidative stress and executed upon disruption of the balance between the transcriptional induction of protective genes and accumulation of iron-mediated damage. BACH1 is suggested to control the threshold of
ferroptosisand to be a therapeutic target for palliating myocardial infarction.
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