NUPR1 is a critical repressor of ferroptosis

Jiao Liu, Xinxin Song, Feimei Kuang, Qiuhong Zhang, Yangchun Xie, Rui Kang, Guido Kroemer () and Daolin Tang ()
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Jiao Liu: Guangzhou Medical University
Xinxin Song: UT Southwestern Medical Center
Feimei Kuang: Guangzhou Medical University
Qiuhong Zhang: University of Pittsburgh
Yangchun Xie: Central South University
Rui Kang: UT Southwestern Medical Center
Guido Kroemer: Sorbonne Paris Cité
Daolin Tang: Guangzhou Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-20904-2

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