Npffr2, the neuropeptide FF receptor 2, is a G protein-coupled receptor (GPCR) that helps regulate pain, modulates the opioid system, and is involved in controlling energy balance, thermogenesis, and the hypothalamic-pituitary-adrenal (HPA) axis [2,4,5,6]. It may also be associated with the RhoA/YAP signaling pathway in cancer [2]. Genetic models, such as knockout mice, are valuable for studying its functions.

In NPFFR2-deficient mice, several phenotypes were observed. Those fed a high-fat diet developed severe glucose intolerance, along with hypothalamic insulin resistance, due to reduced insulin pathway signaling proteins [1]. In hepatocellular carcinoma, silencing of NPFFR2 decreased cancer cell malignancy, while overexpression increased invasion, migration, and anchorage-independent cell growth, suggesting its role in promoting cancer progression [2]. NPFFR2-knockout mice also showed resistance to LPS-induced depressive-like behaviors and stress-exposure-induced anxiety-like behaviors and HPA axis hyperactivity [3,4].

In conclusion, Npffr2 plays essential roles in metabolism, cancer malignancy, stress-related disorders, and pain modulation. Studies using NPFFR2-knockout mouse models have provided insights into its functions in these disease-related processes, offering potential targets for treating conditions such as diabetes, hepatocellular carcinoma, depression, and anxiety-related disorders.