Egl-9 family hypoxia-inducible factor 3 (PHD3)

Egl-9 family hypoxia-inducible factor 3 (PHD3) is a member of the alpha-ketoglutarate-dependent dioxygenase family that functions as a critical oxygen sensor in mammalian cells [1, 2]. Under normal oxygen tension, PHD3 hydroxylates specific proline residues on the Hypoxia-Inducible Factor (HIF) alpha subunits, facilitating their recognition by the von Hippel-Lindau (VHL) tumor suppressor and subsequent proteasomal degradation [1, 4]. During hypoxia, the catalytic activity of PHD3 is diminished, leading to the stabilization and nuclear translocation of HIF-alpha, which drives the expression of genes involved in erythropoiesis, such as erythropoietin (EPO), and iron metabolism [3, 4]. This mechanism has been therapeutically exploited through the development of HIF prolyl hydroxylase (HIF-PH) inhibitors, which are primarily used to treat anemia in patients with chronic kidney disease [3, 5]. While these drugs target multiple PHD isoforms, PHD3 is notably highly inducible by hypoxia and plays a distinct role in regulating HIF-2 alpha and muscle cell differentiation [1, 2]. Beyond renal anemia, PHD3 is a target of interest in cardiovascular ischemia and oncology, although its role in cancer is complex and can be either pro- or anti-tumorigenic depending on the cellular context [4].

Other names

Prolyl hydroxylase domain-containing protein 3PHD3EGLN3HIF-PH3HPH-1Hypoxia-inducible factor prolyl hydroxylase 3

HIF-PH3 inhibitors act by competitively binding to the 2-oxoglutarate binding site of the enzyme, preventing the hydroxylation and subsequent degradation of HIF-alpha subunits, which leads to the activation of the hypoxia response pathway and increased endogenous erythropoietin production [3, 4].