NUPR1 is a critical repressor of ferroptosis

Nat Commun. 2021 Jan 28;12(1):647. doi: 10.1038/s41467-021-20904-2.

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.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Ferroptosis / genetics*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Iron / metabolism*
  • Kaplan-Meier Estimate
  • Lipocalin-2 / genetics*
  • Lipocalin-2 / metabolism
  • Mice, Knockout
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / therapy
  • Piperazines / pharmacology
  • RNAi Therapeutics / methods
  • Signal Transduction / genetics
  • Thiazines / pharmacology
  • Xenograft Model Antitumor Assays / methods

Substances

  • DNA-Binding Proteins
  • Lipocalin-2
  • NUPR1 inhibitor ZZW-115
  • Neoplasm Proteins
  • Nupr1 protein, mouse
  • Piperazines
  • Thiazines
  • Lcn2 protein, mouse
  • Iron