NUPR1 is a critical repressor of ferroptosis - Sorbonne Université
Journal Articles Nature Communications Year : 2021

NUPR1 is a critical repressor of ferroptosis

Abstract

Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in ferroptosis, although the key regulator for ferroptosis in iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, a stress-inducible transcription factor, as a driver of ferroptosis resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic cell death through diminishing iron accumulation and subsequent oxidative damage. Consequently, LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, whereas transfection-enforced re-expression of LCN2 restores resistance to ferroptosis in NUPR1-deficient cells. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn2 conditional knockout mice, or the small molecule ZZW-115) increases the activity of the ferroptosis inducer erastin and worsens pancreatitis, in suitable mouse models. These findings suggest a link between NUPR1-regulated iron metabolism and ferroptosis susceptibility.
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Dates and versions

hal-03127104 , version 1 (01-02-2021)

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Jiao Liu, Xinxin Song, Feimei Kuang, Qiuhong Zhang, Yangchun Xie, et al.. NUPR1 is a critical repressor of ferroptosis. Nature Communications, 2021, 12 (1), pp.647. ⟨10.1038/s41467-021-20904-2⟩. ⟨hal-03127104⟩
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