转录因子
抑制因子
小发夹RNA
程序性细胞死亡
细胞生物学
调节器
下调和上调
癌症研究
诱导剂
生物
细胞凋亡
基因敲除
基因
遗传学
作者
Jiao Liu,Xinxin Song,Feimei Kuang,Liqun Zhang,Yangchun Xie,Rui Kang,Guido Kroemer,Daolin Tang
标识
DOI:10.1038/s41467-021-20904-2
摘要
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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