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

Hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) enzymes are a family of iron-dependent, 2-oxoglutarate-dependent dioxygenases that function as the primary oxygen sensors in mammalian cells (UniProt: Q9GZT9, Q96KS0, Q9H6Z9). Under normal oxygen conditions (normoxia), these enzymes hydroxylate specific proline residues on the alpha subunit of hypoxia-inducible factor (HIF-α), marking it for recognition by the von Hippel-Lindau (VHL) E3 ubiquitin ligase complex and subsequent proteasomal degradation (PubMed: 31633894). When oxygen levels drop (hypoxia), the activity of HIF-PHD is reduced, leading to the stabilization and accumulation of HIF-α. This stabilized HIF-α translocates to the nucleus, where it dimerizes with HIF-β and initiates the transcription of genes responsible for erythropoiesis, such as erythropoietin (EPO), as well as genes involved in iron metabolism and angiogenesis (StatPearls: NBK564374). Therapeutic targeting of HIF-PHD enzymes with small-molecule inhibitors mimics the physiological response to hypoxia, thereby stimulating endogenous EPO production and improving iron utilization (PubMed: 33510439). These inhibitors, such as roxadustat and daprodustat, are primarily used to treat anemia in patients with chronic kidney disease (CKD). However, because HIF regulates a wide array of genes, long-term inhibition raises concerns regarding cardiovascular safety, thromboembolic events, and potential oncogenic effects due to sustained angiogenesis (PubMed: 34133857).

Other names

Prolyl hydroxylase domain-containing proteinEgl nine homologEGLNHIF prolyl-4-hydroxylaseHIF-PH

Reversible inhibition of HIF prolyl hydroxylase enzymes, preventing the hydroxylation and subsequent degradation of HIF-α subunits, leading to increased endogenous erythropoietin production.