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

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) is a family of enzymes, primarily including PHD1, PHD2, and PHD3, that act as critical oxygen sensors in human cells (UniProt Q9GZT9, 2024). Under normoxic conditions, these enzymes hydroxylate specific proline residues on the hypoxia-inducible factor alpha (HIF-alpha) subunit, marking it for ubiquitination and subsequent proteasomal degradation (Sanghani & Haase, JBC, 2022). When oxygen levels are low or when the enzyme is inhibited, HIF-alpha stabilizes and translocates to the nucleus to form a functional transcription factor complex (Maxwell & Eckardt, Nat Rev Nephrol, 2023). This complex activates the expression of genes responsible for the adaptive response to hypoxia, most notably erythropoietin and proteins involved in iron metabolism (Haase, Kidney Int, 2021). In clinical medicine, HIF-PH is a major therapeutic target for treating anemia associated with chronic kidney disease (StatPearls, 2023). Drugs known as HIF-PH inhibitors mimic the hypoxic response to stimulate endogenous erythropoietin production and improve iron utilization (FDA Jesduvroq Label, 2023). While effective in raising hemoglobin levels, these agents require monitoring due to potential risks of cardiovascular events and theoretical concerns regarding the promotion of angiogenesis in malignancies (Chen et al., Lancet, 2019).

Other names

Egl nine homologEGLNProlyl hydroxylase domain-containing proteinPHDHIF prolyl-4-hydroxylase

Inhibition of HIF prolyl hydroxylase enzymes prevents the degradation of HIF-alpha subunits, leading to their stabilization and translocation to the nucleus. This induces the transcription of genes involved in erythropoiesis, such as erythropoietin (EPO) and iron transport proteins (Sanghani & Haase, JBC, 2022; Maxwell & Eckardt, Nat Rev Nephrol, 2023).