AMPD3 encodes adenosine monophosphate deaminase 3, a metabolic enzyme that catalyzes AMP catabolism and plays a critical role in cellular energy metabolism 1. The protein exhibits AMP deaminase activity and participates in IMP biosynthesis and AMP metabolic processes [UniProt]. AMPD3 expression is controlled by three tandem promoters with tissue-specific regulation, particularly in skeletal muscle 2. Mechanistically, AMPD3 functions within the erythrocyte ENT1-AMPD3 axis as a master purinergic hypoxia sensor. Under hypoxic conditions, AMPD3 activation promotes metabolic reprogramming through AMPK-dependent pathways, regulating energy supply and oxygen delivery 1. In cancer contexts, AMPD3 downregulation correlates with advanced tumor stages and poor prognosis in head and neck squamous cell carcinoma, suggesting antiproliferative functions 3. In diabetic hearts, miR-301b-mediated translational suppression of AMPD3 is dysregulated, leading to pathological AMPD3 upregulation and ATP depletion 4. Disease relevance includes adenosine monophosphate deaminase deficiency (erythrocyte type), hypoalphalipoproteinemia with damaging AMPD3 variants identified in low HDL-C populations 5, chr11 kidney disease progression where AMPD3 deficiency is protective 1, and autosomal dominant polycystic kidney disease where super-enhancer-driven AMPD3 upregulation promotes cystogenesis 6. AMPD3 represents a therapeutic target for metabolic dysfunction in multiple pathological contexts.