NUCKS1, also known as Nuclear Casein and Cyclin-dependent Kinase Substrate 1, is a 27 kD chromosomal, highly conserved, vertebrate-specific protein. It is predominantly localized to the nucleus and is one of the most heavily modified proteins in the human proteome. NUCKS1 is involved in modulating chromatin architecture and transcription, DNA repair, cell cycle regulation, and metabolism. It is similar to the high-mobility group (HMG) family and is a RAD51 associated protein 1 (RAD51AP1) paralog, playing a significant role in homologous recombination (HR) and genome stability. It is also a transcriptional regulator of the insulin signaling components [1,2].

In endometriosis, NUCKS1 is highly expressed, and its inhibition decreases cell viability, migration, and increases apoptosis. NUCKS1 promotes the progress of endometriosis through activating PI3K and NF-κB pathways, with VEGF also involved [3]. In osteosarcoma, depletion of NUCKS1 decreased cell proliferation and metastasis, while overexpression accelerated cell aggressiveness by facilitating asparagine synthesis [4]. In colorectal cancer, NUCKS1 knockdown induces cell cycle arrest, inhibits proliferation, and promotes apoptosis and autophagy by activating the PI3K/AKT/mTOR signaling pathway [5]. In gastric cancer, NUCKS1 enhances cell aggressiveness via the PI3K/Akt/mTOR signaling pathway in an IGF-1R-dependent manner [6]. In lung adenocarcinoma, upregulation of NUCKS1 is associated with a poor prognosis [7].

In conclusion, NUCKS1 is a multifunctional protein with key roles in various biological processes such as DNA repair, cell cycle regulation, and metabolism. Through loss-of-function experiments in different cell models, it has been shown to play important roles in multiple diseases including endometriosis, osteosarcoma, colorectal cancer, gastric cancer, and lung adenocarcinoma. These findings contribute to understanding the disease mechanisms and may provide potential therapeutic targets.