EGLN3 (egl-9 family hypoxia inducible factor 3) is a prolyl hydroxylase that serves as a cellular oxygen sensor by catalyzing the hydroxylation of proline residues in multiple target proteins 1. Under normoxic conditions, EGLN3 hydroxylates hypoxia-inducible factor alpha proteins (HIF1A and HIF2A) at specific oxygen-dependent degradation domains, targeting them for proteasomal degradation via the von Hippel-Lindau ubiquitination complex 1. During hypoxia, this hydroxylation is attenuated, allowing HIFs to escape degradation and activate hypoxia-responsive gene expression 1. Beyond HIF regulation, EGLN3 hydroxylates pyruvate kinase M2 (PKM2), enhancing its function as a HIF-1 coactivator and promoting glucose metabolism reprogramming in cancer cells 1. EGLN3 also hydroxylates TFAM, a regulator of mitochondrial biogenesis, with VHL protein stabilizing hydroxylated TFAM 2. Clinically, EGLN3 is implicated in multiple pathological conditions. It is overexpressed in lung adenocarcinoma and predicts resistance to both immunotherapy and chemotherapy 3. In pulmonary hypertension, endothelial EGLN3 upregulation promotes vascular remodeling through EGFR-mediated PI3K/AKT and MAPK pathway activation 4. Additionally, EGLN3 contributes to chr14 airway epithelial hypoxia in muco-obstructive lung diseases by promoting mucus hyperconcentration 5.