Nupr1, also known as Nuclear Protein 1, p8 or Com-1, is a small, intrinsically disordered protein and a stress-inducible transcription factor. It participates in regulating multiple cellular processes such as DNA repair, endoplasmic reticulum stress, oxidative stress response, cell cycle, autophagy, apoptosis, ferroptosis and chromatin remodeling [3]. Nupr1-regulated pathways are crucial in maintaining redox homeostasis and cell survival under stress conditions, and its abnormal expression is associated with various cancers [1,3,4]. Genetic models, like gene knockout mouse models, are valuable tools for studying its functions.

In the context of ferroptosis, Nupr1 was identified as a driver of ferroptosis resistance. Mechanistically, Nupr1-mediated LCN2 expression blocks ferroptotic cell death by reducing iron accumulation and oxidative damage. 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 mouse models, suggesting a link between Nupr1-regulated iron metabolism and ferroptosis susceptibility [2]. In pancreatic cancer, genetic inactivation of the Nupr1 gene antagonizes tumor growth [5].

In conclusion, Nupr1 is a critical regulator in multiple biological processes, especially in redox-related pathways and ferroptosis. Gene knockout and conditional knockout mouse models have been instrumental in revealing its role in pancreatitis and cancer, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Huang, Can, Santofimia-Castaño, Patricia, Iovanna, Juan. 2021. NUPR1: A Critical Regulator of the Antioxidant System. In Cancers, 13, . doi:10.3390/cancers13153670. https://pubmed.ncbi.nlm.nih.gov/34359572/

2. Liu, Jiao, Song, Xinxin, Kuang, Feimei, Kroemer, Guido, Tang, Daolin. 2021. NUPR1 is a critical repressor of ferroptosis. In Nature communications, 12, 647. doi:10.1038/s41467-021-20904-2. https://pubmed.ncbi.nlm.nih.gov/33510144/

3. Liu, Shan, Costa, Max. 2022. The role of NUPR1 in response to stress and cancer development. In Toxicology and applied pharmacology, 454, 116244. doi:10.1016/j.taap.2022.116244. https://pubmed.ncbi.nlm.nih.gov/36116561/

4. Martin, Tracey A, Li, Amber Xinyu, Sanders, Andrew J, Hargest, Rachel, Jiang, Wen G. 2021. NUPR1 and its potential role in cancer and pathological conditions (Review). In International journal of oncology, 58, . doi:10.3892/ijo.2021.5201. https://pubmed.ncbi.nlm.nih.gov/33760183/

5. Santofimia-Castaño, Patricia, Xia, Yi, Peng, Ling, Neira, José Luis, Iovanna, Juan. 2019. Targeting the Stress-Induced Protein NUPR1 to Treat Pancreatic Adenocarcinoma. In Cells, 8, . doi:10.3390/cells8111453. https://pubmed.ncbi.nlm.nih.gov/31744261/