Celebrating a Century of Relaxin: Molecular, Physiological and Clinical Advances in the Relaxin Family Peptide System

Relaxin was first described a century ago as a reproductive hormone of pregnancy. It is now recognised as one member of a family of insulin-like peptide hormones - relaxin-1, relaxin-2, relaxin-3, INSL3, INSL4, INSL5, and INSL6 - signaling through four dedicated G protein-coupled receptors, RXFP 1to4, with relaxin-2 additionally functioning via the glucocorticoid receptor. Work over recent decades has moved the field far beyond reproduction: RXFP1 activation limits fibrosis and remodeling of the extracellular matrix, relaxin-2 has been tested clinically in heart failure, relaxin-3 and INSL5 have emerged as central and gut-derived neuroendocrine signals, and INSL3 is now an established biomarker of Leydig cell functional capacity across the male lifespan. The emerging roles of these 7 relaxin-family peptides have already redefined previously established physiological and regulatory mechanisms. Despite this progress, the field remains fragmented. Receptor activation mechanisms are only partly resolved, translation of relaxin into durable therapeutics has proved difficult, a lack of valid standardized assays remains a persistent obstacle to comparing clinical data, and the physiological roles of several family members are still poorly defined.This Research Topic brings the relaxin field together in a single, integrated collection that reflects how far the biology has travelled in one hundred years and where it is heading next. It aims to connect the molecular and structural understanding of RXFP receptors with the physiological and clinical consequences of their activation, so that advances in receptor pharmacology, endocrine physiology, and translational medicine are read side by side rather than in isolation. We particularly wish to address three persistent gaps: how ligand-receptor structural insight can be converted into selective, stable and clinically useful agonists and antagonists; how relaxin family signaling is integrated across endocrine, cardiovascular, neuroendocrine and reproductive systems; and how assay validation and biomarker standardization can put the field on a firmer quantitative footing. By pairing authoritative synthesis with new primary data, this collection is intended to serve both as a reference point for established investigators and as an accessible entry point for researchers new to relaxin family peptides and their receptors.We welcome Original Research, Reviews, Mini Reviews, Systematic Reviews, Perspectives and Methods articles addressing, but not limited to:● Molecular and structural endocrinology of RXFP1, 2, 3 and 4: activation mechanisms, ligand recognition, structural modelling, and design of selective agonists, antagonists, nanobodies and mini-protein modulators, also including the intriguing activation of glucocorticoid receptors● Endocrine control of fibrosis and extracellular matrix remodeling in renal, hepatic, cardiac, pulmonary, uterine and tumour tissue● Cardiovascular endocrinology of relaxin, including myocardial function, vascular haemodynamics, and translational and clinical trial evidence● Neuroendocrine roles of relaxin-3 and INSL5, covering central circuits, stress adaptation and gut-brain signaling● INSL3/RXFP2 biology across the lifespan, reproductive endocrinology, and comparative physiology across species● Applications of "one health" approaches to highlight the evolving physiology of the relaxin family of insulin-like peptides and their receptors across diverse vertebrates and invertebrates● Clinical biomarker development, antibodies and assay validation for relaxin family peptides across species and matrices Topic editors: Richard Ivell, Robert Bennett, Ravinder Anand-Ivell, Laura Goldsmith Source: https://www.frontiersin.org/research-topics/85013/celebrating-a-century-of-relaxin-molecular-physiological-and-clinical-advances-in-the-relaxin-family-peptide-system