{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe NPPC gene encodes the precursor to C‐type natriuretic peptide (CNP), which must be proteolytically processed—primarily by the endoprotease furin—to yield a mature, biologically active hormone. Once processed, CNP acts locally in an autocrine/paracrine manner by binding to its receptors (for example, GC‐B), thereby stimulating cyclic GMP production to regulate a range of physiological processes. This fundamental processing and signaling mechanism lays the groundwork for its diverse functions across tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCNP plays a critical role in skeletal development and endochondral ossification. Genetic variation in the NPPC gene has been linked to human stature: increased or mis‐regulated NPPC expression (for example, resulting from chromosomal translocations) correlates with skeletal overgrowth and tall stature, whereas loss‐of‐function mutations cause autosomal dominant short stature. Moreover, circulating levels of NT‐proCNP—a stable product of proCNP processing—positively correlate with growth velocity and bone turnover markers, underscoring CNP’s pivotal role in orchestrating growth plate chondrocyte proliferation and differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond skeletal growth, NPPC‐derived CNP is a key modulator of cardiovascular homeostasis. It exerts potent vasorelaxant and anti‐inflammatory actions by suppressing leukocyte–endothelial interactions, reducing P‐selectin expression, and inhibiting platelet aggregation. In conditions of hemodynamic stress or ischemia, cardiac and vascular production of CNP is up‐regulated, reinforcing its cardioprotective roles in mitigating myocardial ischemia/reperfusion injury, aortic valve calcification, and adverse cardiac remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its well‐characterized roles in growth and cardiovascular regulation, NPPC‐derived CNP participates in several other physiological domains. It influences chondrogenic differentiation of mesenchymal stem cells and contributes to the regulation of extracellular matrix synthesis. In the reproductive system, CNP modulates sperm motility and acrosome reaction, while in adipose tissue it appears to play a role in adipogenesis and may serve as a biomarker for obesity‐related endothelial dysfunction. Expression studies also reveal CNP involvement in the anterior pituitary, ocular lens epithelium, and renal as well as epididymal tissues, where it is subject to regulation by various intracellular signaling cascades (such as MAPK and PKG pathways)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Chengliang Wu, Faye Wu, Junliang Pan, et al. 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