PROK2 (prokineticin 2) is a secreted neuropeptide that functions through G-protein coupled receptors (PROKR1/PROKR2) to regulate multiple physiological systems. In the nervous system, PROK2 encodes pleasant touch sensation by signaling through spinal PROKR2+ interneurons, with deficiency impairing stress responses and prosocial behaviors 1. PROK2 also protects neurons from ferroptosis-mediated cell death in traumatic brain injury by suppressing lipid peroxidation through Fbxo10-driven ACSL4 degradation 2. Beyond the nervous system, PROK2 regulates gastrointestinal smooth muscle contraction 3, promotes angiogenesis, modulates circadian rhythms, and influences immune responses 3. In reproduction, PROK2/PROKR2 mutations cause Kallmann syndrome (hypogonadotropic hypogonadism with anosmia) through impaired GnRH neuron migration 4. Heterozygous mutations show incomplete penetrance with variable phenotypes ranging from isolated hypogonadism to combined anosmia/hypogonadism 4. Recently, PROK2+ neutrophil infiltration was identified in colorectal cancer liver metastases, where these cells promote immunosuppression and poor prognosis 5. Clinical studies reveal rare PROK2/PROKR2 variants associate with reproductive dysfunction and gastrointestinal phenotypes in general populations 6.