Rxfp3, the relaxin-family peptide receptor 3, is a G -protein-coupled receptor. It is a key component of the relaxin-3/RXFP3 system which belongs to the relaxin/insulin superfamily. This system is involved in multiple important physiological processes such as stress responses, appetite control, motivation for reward, and also has a role in modulating neuroendocrine function related to stress, feeding, and metabolism [2,4]. It may also be associated with DNA damage response and repair processes, as its expression is affected by DNA damage and oxidative stress [1,5].

Studies in rats have shown that the RXFP3-selective negative allosteric modulator RLX-33 reduces alcohol self-administration, suggesting a role for RXFP3 in alcohol use disorder treatment [3]. Additionally, overexpression or stimulation of RXFP3 by its endogenous ligand relaxin 3 (RLN3) can regulate the DNA damage response and repair processes, and RLN3 has been linked to multiple aging-related disease processes [1]. Analyses in GIT2KO mice demonstrated that GIT2 expression affects RXFP3, indicating a therapeutically-targetable system related to metabolic aging processes [5].

In conclusion, Rxfp3 is involved in a wide range of biological functions, from physiological regulation like stress and appetite control to playing a role in aging-related diseases and potentially in alcohol use disorder. The use of animal models, such as GIT2KO mice and rats treated with RXFP3 modulators, has been crucial in uncovering these functions and highlighting the potential of Rxfp3 as a therapeutic target in related disease areas.