EGLN2 (egl-9 family hypoxia inducible factor 2) is a prolyl hydroxylase that functions as a critical cellular oxygen sensor. Under normoxic conditions, EGLN2 catalyzes hydroxylation of proline residues in target proteins including HIF1A and HIF2A at their oxygen-dependent degradation domains, targeting them for proteasomal degradation via the von Hippel-Lindau complex 123. During hypoxia, reduced EGLN2 activity allows HIF stabilization, nuclear translocation, and activation of hypoxia-responsive genes 123. Beyond HIF regulation, EGLN2 hydroxylates additional substrates including CEP192 (regulating cilia formation) and mediates NF-κB activation under hypoxic conditions 45. Clinically, EGLN2 dysregulation associates with multiple diseases. In amyotrophic lateral sclerosis, EGLN2 downregulation protects motor neurons by normalizing astrocytic interferon signaling 6. EGLN2 inhibition also promotes ferroptosis in cancer cells through ARNTL-mediated pathways 7, while YAP1-mediated EGLN2 suppression drives aerobic glycolysis in pancreatic cancer 8. In kidney disease, concurrent PHD inactivation (including EGLN2) promotes maladaptive repair through glycolysis-dependent mechanisms 9. EGLN2 promoter polymorphisms associate with cancer risk, particularly digestive system malignancies in Asian populations 10. EGLN2 DNA methylation correlates with lung adenocarcinoma prognosis through HIF1A interaction 11.