- Prolyl hydroxylase domain protein 3 (PHD3), also known as EGLN3, is one of the three main isoforms of the prolyl hydroxylase family that regulate hypoxia-inducible factor (HIF) stability in response to oxygen availability.
- Like PHD1 and PHD2, PHD3 is an oxygen-, Fe²⁺-, and 2-oxoglutarate–dependent dioxygenase that hydroxylates conserved proline residues in the oxygen-dependent degradation domain (ODD) of HIF-α subunits. Under normoxic conditions, this modification promotes recognition of HIF-α by the von Hippel–Lindau (pVHL) tumor suppressor protein, targeting HIF-α for ubiquitination and proteasomal degradation. Under hypoxia, when oxygen is insufficient for hydroxylation, PHD3 activity decreases, allowing HIF-α to stabilize, accumulate, and activate hypoxia-responsive gene expression.
- Among the PHD isoforms, PHD3 is unique in being strongly induced by hypoxia itself, largely under the control of HIF signaling. This positive feedback regulation ensures that PHD3 acts as a delayed “shut-off” mechanism: once oxygen levels are restored, elevated PHD3 expression accelerates HIF-α degradation to reset the system. Because of this property, PHD3 is often considered a stress-responsive enzyme, upregulated in prolonged hypoxia and in tissues experiencing frequent oxygen fluctuations. Its expression is particularly enriched in the heart, lungs, brain, and certain endocrine tissues, where precise control of oxygen homeostasis is critical.
- Beyond its canonical role in HIF regulation, PHD3 participates in a variety of cellular processes, some of which are HIF-independent. It has been implicated in regulating apoptosis, neuronal differentiation, and metabolic adaptation to stress. In neuronal and neuroendocrine cells, PHD3 appears to promote programmed cell death under conditions of growth factor withdrawal or prolonged hypoxia, highlighting its role as a mediator of cell fate decisions. In immune cells, PHD3 influences inflammatory responses, possibly by modulating NF-κB and other non-HIF pathways. These broader functions suggest that PHD3 contributes to fine-tuning adaptive and maladaptive responses to stress.
- PHD3 has also attracted significant attention in the context of disease. In cancer biology, PHD3 exhibits complex and context-dependent roles. On one hand, loss or downregulation of PHD3 can contribute to tumor progression by permitting sustained HIF activation and enhanced angiogenesis. On the other hand, overexpression of PHD3 has been linked to increased apoptosis and tumor suppression in certain malignancies, particularly neuroendocrine tumors. Similarly, in cardiovascular disease, PHD3 induction in the heart during chronic hypoxia or ischemia can influence cell survival and remodeling. These dual roles underscore the delicate balance PHD3 maintains between promoting survival under transient hypoxia and driving cell death during prolonged stress.
- From a therapeutic standpoint, PHD3 has been explored as a target for both inhibition and activation, depending on the disease context. Like PHD2, PHD3 is inhibited by small-molecule prolyl hydroxylase inhibitors (HIF-PHIs) developed to treat anemia in chronic kidney disease, where transient stabilization of HIF activity is beneficial. However, in cancer, strategies to restore or enhance PHD3 expression are being investigated to counteract tumor growth by re-engaging its tumor-suppressive or pro-apoptotic functions. The duality of PHD3’s roles highlights the need for context-specific therapeutic approaches.
