NOSTRIN, short for nitric oxide synthase traffic inducer, is a pleiotropic regulator of endothelial cell function. It interacts with endothelial nitric oxide synthase (eNOS), modulating its subcellular distribution and NO release [7]. It also participates in multiple pathways such as those related to cell proliferation, inflammation, and angiogenesis, thus being of great biological importance. Genetic models, especially knockout models, can be valuable for studying its functions.

In murine trophoblast cells, NOSTRIN levels increase during gestation. Precocious over-expression of NOSTRIN leads to increased trophoblast giant cell (TGC) formation and invasion, as it affects the G/F actin ratio and forms complexes with proteins like N-WASP, Dynamin, and Cdk1 [1]. In cirrhosis and acute-on-chronic liver failure (ACLF) models, hepatic Nostrin expression is elevated, and its knockdown in human umbilical vein endothelial cells (HUVECs) improves eNOS activity and reduces inflammation [2]. In a benign prostatic hyperplasia (BPH) mouse model, NOSTRIN expression is inhibited. Over-expressing NOSTRIN in prostate epithelial cells inhibits proliferation, oxidative stress, and inflammation, possibly through NF-κB signaling [3]. In colon cancer cell lines, NOSTRIN over-expression reduces cell invasion, colony formation, and stemness, while its knockdown enhances metastatic potential [4]. In acute kidney injury (AKI) patients, serum Nostrin levels are higher and are associated with in-hospital death, need for kidney replacement therapy, and lack of kidney function recovery [5]. In cirrhotic patients, Nostrin expression is increased, reducing eNOS activity and local NO generation, and blood Nostrin concentration may be a biomarker for disease severity [6]. In end-stage chronic kidney disease (CKD) patients, serum Nostrin levels are further increased compared to AKI patients, indicating impaired turnover [8]. In zebrafish and mice, NOSTRIN is necessary for proper vascular development, as it impacts endothelial tip cell migration and filopodia formation, and is involved in FGF-2-dependent Rac1 activation [9].

In conclusion, NOSTRIN plays diverse and crucial roles in multiple biological processes and disease conditions. Through model-based research, especially in KO/CKO mouse models or other loss-of-function experiments, its functions in processes like trophoblast differentiation, liver disease development, BPH, colon cancer progression, kidney injury and disease, and vascular development have been revealed. These findings contribute to understanding the underlying mechanisms of these diseases and may provide potential therapeutic targets.