Ntsr1, short for neurotensin receptor 1, is a G protein-coupled receptor (GPCR). It is involved in various biological processes, with its endogenous ligand being neurotensin (NTS). Ntsr1 signals through canonical G protein activation and engages β-arrestins, mediating distinct cellular signaling events. It is associated with pathways like IP3/Ca2 + /PKC/MAPKs, MMPs/EGFR/MAPKs (PI3K/Akt), Rho-GTPases and non-receptor tyrosine kinase pathways, and is important in processes such as the regulation of dopamine neuronal activity, opioid-independent analgesia, food intake, and in tumor-related processes [1,5].

In animal models, a β-arrestin-biased allosteric modulator of Ntsr1, SBI-553, selectively attenuates addictive behaviors without the severe side effects of balanced Ntsr1 agonism, indicating that Ntsr1 G protein and β-arrestin activation have separable physiological effects [1]. In rat models of pulmonary hypertension (PH), Ntsr1 was found to contribute to PH by enhancing endoplasmic reticulum stress via the JAK2-STAT3-Thbs1 signaling pathway, and knockdown of Ntsr1 reversed the PH phenotype [2]. In lung cancer studies, knockdown of Ntsr1 reduced cancer cell migration and invasion, and in lung adenocarcinoma, Ntsr1 promoted epithelial-mesenchymal transition and metastasis through the Wnt/β-catenin pathway [3,4]. In gastric adenocarcinoma cells, disruption of Ntsr1 reduced cell proliferation and invasion, and Ntsr1 interacted with other genes like MET and EGFR/HER2 in the oncogenesis process [6].

In conclusion, Ntsr1 plays essential roles in multiple biological functions and disease conditions. Studies using animal models, especially those involving knockdown or modulation of Ntsr1, have revealed its significance in drug addiction, pulmonary hypertension, and various cancers. These findings highlight Ntsr1 as a potential therapeutic target in these disease areas.