RXFP4

RXFP4 (relaxin family peptide receptor 4) is a class A G protein-coupled receptor and the cognate receptor for insulin-like peptide 5 (INSL5), functioning as a key mediator of gut-brain and metabolic signaling pathways^[1][2]. Mechanistically, RXFP4 predominantly couples to Gα_i/o proteins, resulting in inhibition of cAMP accumulation while promoting activation of ERK1/2, p38 MAPK, Akt, and S6 ribosomal protein signaling, thereby linking extracellular peptide sensing to cellular metabolic and transcriptional responses^[3][4]. The INSL5-RXFP4 axis is highly enriched in the gastrointestinal tract and has been implicated in the regulation of food intake, feeding preference, gut motility, and glucose homeostasis, supporting its relevance to metabolic disease research and neuroendocrine physiology^[2][5][6]. Experimental studies further demonstrated that RXFP4-expressing hypothalamic neurons regulate intake of high-fat and highly palatable foods, identifying a central mechanism through which RXFP4 influences feeding behavior^[5]. In the gut, RXFP4 is highly expressed in enterochromaffin cells, where receptor activation suppresses cAMP signaling, reduces TPH1 expression, and modulates serotonin production and release, establishing a mechanistic connection between RXFP4 signaling and intestinal neuroendocrine regulation^[6]. Compared with the closely related receptor RXFP3, RXFP4 displays distinct ligand recognition and subtype-selective pharmacology despite partial responsiveness to relaxin-3, highlighting important receptor-specific signaling properties for mechanistic studies^[4]. Structural and pharmacological investigations have identified both peptide and small-molecule RXFP4 agonists, including INSL5-derived ligands and subtype-selective compounds, which serve as valuable tools for dissecting receptor biology and evaluating therapeutic potential in metabolic and gastrointestinal disease models^[4][7].