The Third Affiliated Hospital, Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, 510600, Guangdong, China.
Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
Nat Commun. 2021 Jan 28;12(1):647. doi: 10.1038/s41467-021-20904-2.
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.
铁死亡是一种铁依赖性的调节性细胞死亡，代表了一种新兴的疾病调节机制。转录因子在铁死亡中发挥多种作用，尽管铁代谢中铁死亡的关键调节因子仍难以捉摸。我们使用 NanoString 技术鉴定出应激诱导的转录因子 NUPR1 是铁死亡抵抗的驱动因素。从机制上讲，NUPR1 介导的 LCN2 表达通过减少铁积累和随后的氧化损伤来阻止铁死亡细胞死亡。因此，LCN2 耗竭模拟了 NUPR1 缺陷细胞中对铁死亡诱导的反应，而转染强制表达 LCN2 可恢复 NUPR1 缺陷细胞对铁死亡的抗性。NUPR1-LCN2 通路的药理学或遗传学阻断（使用 NUPR1 shRNA、LCN2 shRNA、胰腺特异性 Lcn2 条件性敲除小鼠或小分子 ZZW-115）增加了铁死亡诱导剂 erastin 的活性，并在合适的小鼠模型中加重了胰腺炎。这些发现表明 NUPR1 调节的铁代谢与铁死亡易感性之间存在联系。
