Nupr1, also known as Nuclear Protein 1, Com-1 or p8, is a small intrinsically disordered protein. It is a stress-inducible transcriptional regulator involved in multiple cellular processes, including DNA repair, endoplasmic reticulum (ER) stress response, oxidative stress response, cell cycle, autophagy, apoptosis, ferroptosis, and chromatin remodeling [3]. Nupr1 participates in regulating redox homeostasis through its impact on mitochondrial function, energy metabolism, and iron metabolism, and is thus crucial for the antioxidant system [1].

In terms of functional studies, genetic or pharmacological blockade of the Nupr1-Lcn2 pathway in suitable mouse models, such as using Nupr1 shRNA, Lcn2 shRNA, pancreas-specific Lcn2 conditional knockout (CKO) mice, or the small molecule ZZW-115, increases the activity of the ferroptosis inducer erastin and worsens pancreatitis, suggesting a link between Nupr1-regulated iron metabolism and ferroptosis susceptibility [2]. In addition, ZZW-115-mediated inhibition of Nupr1-dependent stress granules formation hampered the development of pancreatic intraepithelial neoplasia (PanINs) in Pdx1-cre;LSL-KrasG12D (KC) mice, indicating a potential therapeutic approach in KrasG12D-driven tumors [4]. Also, treatment with ZZW-115, an Nupr1 inhibitor, reversed the tumor-promoting effects of circPIAS1 and sensitized HCC cells to lenvatinib, highlighting the role of Nupr1 in HCC progression through modulation of ferroptosis [5].

In conclusion, Nupr1 is a key regulator in multiple biological processes, especially those related to stress response and cell death pathways. The use of gene knockout (KO) and CKO mouse models has been instrumental in revealing its role in diseases like pancreatitis and cancer, offering potential therapeutic targets for these conditions.