NUPR1 is a critical repressor of ferroptosis

Jiao Liu,Feimei Kuang,Daolin Tang,Guido Kroemer,Xinxin Song,Rui Kang,Yangchun Xie,Qiuhong Zhang

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.

Highlights

Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism
To identify regulators of ferroptosis, we first evaluated the impact of erastin on the expression of 770 tumor-associated genes in two human pancreatic ductal adenocarcinoma (PDAC) cell lines (PANC1 and BxPC3) using NanoString, a digital technology based on direct multiplexed measurement of nucleic acids through fluorescent barcodes[19]
Quantitative polymerase chain reaction confirmed that both erastin and RSL3 induced the upregulation of NUPR1 mRNA in four human PDAC cell lines (PANC1, BxPC3, MiaPaCa2, and CFPAC1), primary human PDAC cells, as well as mouse PDAC cell lines from Pdx1-Cre;K-RasG12D/+ mice (Supplementary Fig. 1a)

Summary

Introduction

Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn[2] 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 NUPR1regulated iron metabolism and ferroptosis susceptibility. Ferroptosis is regulated at multiple levels, including at the level of transcription factors that may modulate the resistance of malignant cells to anticancer drugs[10] Such transcription factors do participate in rapid responses to ferroptotic stimuli, and modulate the long-term outcome of ferroptosis in a context-dependent manner[11]. Pharmacological or genetic blockade of the NUPR1–LCN2 pathway may enhance the anticancer activity of ferroptosis activator and pathologic inflammation in vitro and in vivo

Methods

Results

Conclusion