Hypoxia-inducible factor prolyl hydroxylase 3 (PHD3)

Hypoxia-inducible factor prolyl hydroxylase 3 (PHD3) is an oxygen-, iron-, and 2-oxoglutarate-dependent enzyme that hydroxylates specific proline residues on hypoxia-inducible factor α (HIF-α) subunits under normoxic conditions, marking them for proteasomal degradation through recruitment of the von Hippel-Lindau E3 ubiquitin ligase complex[1][4][5]. During hypoxia or upon pharmacological inhibition, decreased PHD3 activity allows HIF-α stabilization, nuclear translocation, and activation of hypoxia-responsive genes involved in adaptation to low oxygen, erythropoiesis, metabolism, angiogenesis, and cell survival[1][4][5][6][7]. PHD3 is expressed in various tissues, plays a key role in erythropoietin regulation, and is implicated in the pathogenesis of renal anemia and several malignancies, particularly clear cell renal cell carcinoma[5][7]. It is the most hypoxia-sensitive PHD isoform and a validated therapeutic target for anemia, though long-term inhibition may raise oncogenic and cardiovascular risks[2][6][7].

Other names

Prolyl hydroxylase domain-containing protein 3EGLN3HPH-3HIF-PH3Egl nine homolog 3

Inhibition of PHD3 leads to stabilization of HIF-α, enhancing transcription of HIF target genes including erythropoietin, promoting erythropoiesis, and improving cellular adaptation to hypoxia[2][6][8].