ENPP4 is an ectonucleotide pyrophosphatase/phosphodiesterase that hydrolyzes extracellular diadenosine polyphosphates (Ap3A and Ap4A) into nucleotide products, releasing ADP that activates platelet aggregation and promotes blood coagulation 1. Beyond its canonical catalytic function, ENPP4 exhibits non-catalytic roles: it binds phosphatidylserine and regulates kidney patterning during nephrogenesis through s1pr5-mediated signaling independent of enzymatic activity 2. Clinically, ENPP4 has emerged as a significant disease marker across multiple pathologies. In acute myeloid leukemia (AML), ENPP4 is selectively expressed on leukemia stem cells (CD34+CD38-) but absent from normal hematopoietic stem cells and mature monocytes, making it a valuable LSC marker 3. A 4-mRNA prognostic signature including ENPP4 independently predicts overall survival in AML patients and enhances risk stratification beyond traditional factors 1. ENPP4 is implicated in multiple additional disease contexts: it appears as a causal extracellular vesicle-related gene in periodontitis pathogenesis 4, is among the top 10 differentially expressed genes in diabetes 5, correlates with fibrinolytic impairment and thrombotic risk in Klinefelter syndrome 6, serves as a biomarker for smoking-related lung squamous cell carcinoma 7, and associates with autism spectrum disorder across multiple brain regions 8.