{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPROK2 functions as a key circadian output signal in mammals. In the suprachiasmatic nucleus the peptide’s rhythmic, light‐entrained expression helps to coordinate behavioral and physiological rhythms, thereby establishing the proper timing of locomotor activity and additional circadian processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in circadian regulation, PROK2 is critical for proper neuroendocrine reproductive development. It governs olfactory bulb morphogenesis and facilitates the migration of gonadotropin‐releasing hormone (GnRH) neurons—a process whose disruption leads to conditions such as Kallmann syndrome and idiopathic hypogonadotropic hypogonadism. Expression and mutation studies, including analyses in both human patients and mouse models, demonstrate that heterozygous and biallelic defects in PROK2 (or its receptor PROKR2) result in variable reproductive phenotypes accompanied by anosmia. Moreover, its expression in reproductive tissues such as the endometrium and fetal ovary further underscores its involvement in gonadal development and differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPROK2 also exhibits potent angiogenic and tumor‐promoting activities in diverse tissues. Studies have demonstrated that PROK2 acts as an endothelial mitogen, promoting survival, proliferation, and migration of vascular and myeloid cells. Such functions contribute to neovascularization and are implicated in the progression of several malignancies—including prostate, colorectal and cervical cancers—as well as in chronic inflammatory skin disorders like psoriasis. In tumor models, PROK2 secretion enhances the recruitment of myeloid cells and supports a microenvironment conducive to tumor growth and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these roles, PROK2 modulates inflammatory responses and confers neuroprotective effects under pathological conditions. In models of neural injury—such as traumatic brain injury and subarachnoid hemorrhage—increased PROK2 signaling induces a phenotypic shift in astrocytes toward the protective “A2” state, thereby reducing proinflammatory cytokine production and lipid peroxidation that otherwise lead to neuronal ferroptosis. Altered PROK2 dynamics have also been implicated in neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as in persistent olfactory dysfunction following viral infections."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, PROK2 is emerging as an important regulator of energy balance. By acting primarily through its receptor in the amygdala, PROK2 exerts anorexigenic effects that help suppress food intake—a function modulated by accessory proteins such as MRAP2—thereby linking PROK2 signaling to the control of systemic energy homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPROK2 is also involved in peripheral inflammatory regulation and tissue remodeling. In the gastrointestinal tract and airways, the peptide acts in a cytokine‐like manner to modulate ion channel activity and inflammatory responses—evidenced by its up‐regulation in settings such as cystic fibrosis. In the uteroplacental unit, PROK2 is part of the inflammatory cascade that triggers smooth muscle contractility during labor, suggesting its potential as a therapeutic target in preterm birth."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "34", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, recent evidence indicates that PROK2 influences cardiovascular tissue remodeling via epicardium‐derived progenitor cells. By steering these progenitors away from adipogenic fates in favor of a pro‐vasculogenic lineage, PROK2 contributes to neovascularization and the maintenance of cardiac vascular integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Michelle Y Cheng, Clayton M Bullock, Chuanyu Li, et al. 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