Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) (HIF-PH)

Hypoxia-inducible factor prolyl hydroxylases (HIF-PHs) are a family of oxygen-sensing enzymes, primarily including PHD1, PHD2, and PHD3, that regulate the stability of hypoxia-inducible factors (HIFs) [UniProt: Q9GZT9]. Under normoxic conditions, these enzymes use oxygen and 2-oxoglutarate to hydroxylate specific proline residues on the HIF-alpha subunit, marking it for ubiquitination by the von Hippel-Lindau (VHL) E3 ubiquitin ligase and subsequent proteasomal degradation [PubMed: 11206552]. When oxygen levels are low or when the enzymes are pharmacologically inhibited, HIF-alpha accumulates and moves into the nucleus to activate the transcription of genes essential for adapting to hypoxia, most notably erythropoietin (EPO) [StatPearls: NBK564369]. This pathway is a major therapeutic target for treating anemia associated with chronic kidney disease (CKD), as HIF-PH inhibitors can stimulate endogenous EPO production and improve iron homeostasis [PubMed: 31113700]. Clinical use of these inhibitors, such as roxadustat and daprodustat, provides an oral alternative to injectable erythropoiesis-stimulating agents [FDA: 2023]. However, concerns remain regarding the potential for off-target effects, such as the promotion of angiogenesis in tumors or increased risk of cardiovascular complications [PubMed: 33536231].

Other names

Prolyl hydroxylase domain-containing proteinPHDEgl nine homologEGLNHIF prolyl-hydroxylaseEGLN1EGLN2EGLN3

Inhibition of HIF-PH enzymes prevents the hydroxylation of HIF-alpha subunits, leading to their stabilization and translocation to the nucleus. This induces the transcription of the erythropoietin (EPO) gene and other genes involved in iron transport and absorption, thereby stimulating red blood cell production [PubMed: 31113700].