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NUPR1 is a critical repressor of ferroptosis

Author

Listed:
  • 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
    Centre de Recherche des Cordeliers
    Institut National de la Santé et de la Recherche Médicale
    Université Pierre et Marie Curie)

  • Daolin Tang

    (Guangzhou Medical University
    UT Southwestern Medical Center)

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.

Suggested Citation

  • Jiao Liu & Xinxin Song & Feimei Kuang & Qiuhong Zhang & Yangchun Xie & Rui Kang & Guido Kroemer & Daolin Tang, 2021. "NUPR1 is a critical repressor of ferroptosis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20904-2
    DOI: 10.1038/s41467-021-20904-2
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    Cited by:

    1. Zhi Lin & Jiao Liu & Fei Long & Rui Kang & Guido Kroemer & Daolin Tang & Minghua Yang, 2022. "The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Huiqiang Cai & Bin Zhang & Johanne Ahrenfeldt & Justin V. Joseph & Maria Riedel & Zongliang Gao & Sofie K. Thomsen & Ditte S. Christensen & Rasmus O. Bak & Henrik Hager & Mikkel H. Vendelbo & Xin Gao , 2024. "CRISPR/Cas9 model of prostate cancer identifies Kmt2c deficiency as a metastatic driver by Odam/Cabs1 gene cluster expression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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