Hypoxia-inducible factor prolyl-4-hydroxylase 2 (HIF-PH2)

Hypoxia-inducible factor prolyl-4-hydroxylase 2 (HIF-PH2), commonly known as PHD2 or EGLN1, is a critical oxygen-sensing enzyme that regulates the stability of hypoxia-inducible factors (HIFs) (UniProt P59796). Under normoxic conditions, HIF-PH2 uses oxygen, iron, and 2-oxoglutarate to hydroxylate specific proline residues on the HIF-alpha subunit, marking it for ubiquitination by the von Hippel-Lindau (VHL) E3 ligase and subsequent proteasomal degradation (PubMed: 11557882). When oxygen levels are low or the enzyme is pharmacologically inhibited, HIF-alpha stabilizes and translocates to the nucleus to activate the transcription of genes such as erythropoietin (EPO) and those involved in iron transport (PubMed: 31113701). This mechanism has made HIF-PH2 a primary therapeutic target for treating anemia associated with chronic kidney disease (CKD). Small-molecule inhibitors, known as HIF-PHIs, are used to stimulate endogenous EPO production as an alternative to traditional erythropoiesis-stimulating agents (ESAs) (FDA: Jesduvroq Approval). However, because HIF regulates a wide array of genes, safety concerns exist regarding potential off-target effects such as increased risk of thromboembolism, hypertension, and the theoretical risk of promoting tumor angiogenesis (PubMed: 33536231).

Other names

Egl nine homolog 1EGLN1Prolyl hydroxylase domain-containing protein 2PHD2HPH-2HIF-prolyl hydroxylase 2Hypoxia-inducible factor prolyl hydroxylase 2

Inhibition of the HIF prolyl hydroxylase enzyme prevents the hydroxylation and subsequent proteasomal degradation of HIF-alpha subunits, leading to the stabilization of HIF and the induction of erythropoietin (EPO) gene expression and improved iron utilization.