Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2) (PHD2)

Hypoxia-inducible factor prolyl hydroxylase 2 (PHD2), encoded by the EGLN1 gene, is a critical oxygen-sensing enzyme that regulates the stability of hypoxia-inducible factors (HIFs) [1, 3]. Under normoxic conditions, PHD2 utilizes oxygen and 2-oxoglutarate to hydroxylate specific proline residues on HIF-alpha subunits, marking them for ubiquitination and proteasomal degradation via the von Hippel-Lindau (VHL) pathway [4, 15]. When oxygen levels are low, PHD2 activity is inhibited, leading to the stabilization and nuclear translocation of HIF, which subsequently activates the transcription of genes involved in erythropoiesis, angiogenesis, and metabolic adaptation [2, 9]. This pathway is the primary mechanism by which the body maintains oxygen homeostasis and responds to hypoxic stress [5, 14]. Therapeutically, PHD2 is targeted by a class of drugs known as HIF-prolyl hydroxylase inhibitors (HIF-PHIs) to treat anemia associated with chronic kidney disease (CKD) [6, 13]. These inhibitors, such as roxadustat and daprodustat, mimic the hypoxic response to stimulate endogenous erythropoietin production and improve iron utilization [10, 11]. Beyond renal anemia, EGLN1 is implicated in familial erythrocytosis type 3 and has been studied for its complex, context-dependent roles in cancer progression and ischemic tissue repair [8, 12, 17].

Other names

Egl nine homolog 1 [1, 3]Prolyl hydroxylase domain-containing protein 2 [1, 3]HIF-PH2 [1, 4]HPH-2 [1, 3]ZMYND6 [1, 3]SM20 [3, 4]Egl-9 family hypoxia-inducible factor 1 [3, 9]EGLN1 [1, 5]

Reversible inhibition of HIF-prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3), leading to the stabilization and nuclear accumulation of HIF-alpha subunits, which increases endogenous erythropoietin production and improves iron metabolism [2, 6, 10].