ENPP5 (ectonucleotide pyrophosphatase/phosphodiesterase family member 5) is an extracellular enzyme that catalyzes NAD+ hydrolysis 1 and plays roles in multiple physiological processes including bone development, aging, and systemic disease. In skeletal development, ENPP5 is expressed in osteoblasts, odontoblasts, ameloblasts, and periodontal ligament cells, with region-specific expression patterns suggesting site-dependent functions in craniofacial morphogenesis 2. A homozygous missense variant (p.Gly58Val) in the putative active binding site causes a novel skeletal dysplasia featuring premaxillary overgrowth, gingival hyperplasia, and dental hypercementosis, establishing the first clinical link between ENPP5 dysfunction and oro-dental development 2. ENPP5 functions as a senescence-associated secretory phenotype (SASP) factor; its knockdown suppresses SASP in aging fibroblasts and ameliorates age-related skin changes including collagen thinning and subcutaneous adipose tissue loss in mice 1. Genetically, ENPP5 serves as a potential therapeutic target for primary open-angle glaucoma and mediates the causal association between insomnia and chr6 kidney disease, with no identified adverse effects 34. In cancer biology, LINE retroelements compete with tumor-suppressive miR-126 to regulate ENPP5 expression as competing endogenous RNAs 5. Additionally, ENPP5 is downregulated by inflammatory miRNAs in periodontal disease and represents a target gene in stem cell exosome-mediated cartilage development 67.