NUCKS1, also known as Nuclear Casein and Cyclin-dependent Kinase Substrate 1, is a highly conserved, vertebrate-specific, chromatin-associated protein. It has multiple functions including modulating chromatin architecture, transcription, DNA repair, and cell cycle regulation. It is involved in pathways such as homologous recombination, insulin signaling, and is related to the PI3K/AKT/mTOR and NF-κB pathways. Its expression is high in stem cells and the brain, and is developmentally regulated in mice. It is associated with several malignancies, metabolic syndrome, and Parkinson's disease, highlighting its biological importance [1,2].

In endometriosis, NUCKS1 is highly expressed. Inhibition of NUCKS1 in hEM15A cells decreases cell viability and migration, increases apoptosis, and reduces the expression of NF-κB, PI3K, and VEGF, suggesting it promotes endometriosis through activating PI3K and NF-κB pathways [3]. In osteosarcoma, depletion of NUCKS1 decreases cell proliferation and metastasis, while overexpression accelerates cell aggressiveness. NUCKS1 facilitates asparagine synthesis by upregulating ASNS, and LINC00629 promotes NUCKS1 expression by sponging miR-4768-3p [4]. In colorectal cancer, NUCKS1 knockdown induces cell cycle arrest, inhibits proliferation, and promotes apoptosis and autophagy, while overexpression has the opposite effects. NUCKS1 exerts its cancer-promoting function by activating the PI3K/AKT/mTOR signaling pathway [5]. In gastric cancer, NUCKS1 overexpression is related to the invasive phenotype and shortened survival. Depleting NUCKS1 induces apoptosis and reduces cell proliferation and invasiveness, while overexpression enhances these effects. NUCKS1 enhances gastric cancer cell aggressiveness via the PI3K/Akt/mTOR signaling pathway in an IGF-1R-dependent manner [6].

In conclusion, NUCKS1 plays crucial roles in DNA damage response, metabolism, cell cycle regulation, and inflammation-related immune response. Through studies in disease-relevant cell models, NUCKS1 has been shown to be involved in the progression of endometriosis, osteosarcoma, colorectal cancer, and gastric cancer. These findings suggest that understanding NUCKS1 function can provide insights into the mechanisms of these diseases and potentially identify new therapeutic targets.