- Prolyl hydroxylase domain protein 2 (PHD2), also known as EGLN1, is the most critical and widely expressed isoform of the prolyl hydroxylase family responsible for regulating hypoxia-inducible factor (HIF) stability.
- Like PHD1 and PHD3, PHD2 is an Fe²⁺- and 2-oxoglutarate–dependent dioxygenase that hydroxylates specific proline residues within the oxygen-dependent degradation domain (ODD) of HIF-α subunits. This hydroxylation reaction occurs under normoxic conditions and creates a binding site for the von Hippel–Lindau (pVHL) tumor suppressor protein, which recruits the ubiquitin–proteasome machinery to degrade HIF-α. By acting as the primary cellular oxygen sensor, PHD2 ensures that HIF activity is tightly repressed in the presence of sufficient oxygen and becomes activated only under hypoxic stress.
- PHD2 is ubiquitously expressed across tissues and is considered the “gatekeeper” of HIF regulation. Genetic studies have shown that PHD2 is essential for embryonic development in mammals: complete knockout of EGLN1 in mice results in embryonic lethality due to excessive HIF stabilization and uncontrolled angiogenesis. In contrast, partial loss-of-function mutations in humans lead to distinct physiological consequences. For example, germline mutations in EGLN1 have been associated with familial erythrocytosis, a condition characterized by abnormally high red blood cell levels due to chronic HIF-driven erythropoietin (EPO) expression. These findings highlight the central role of PHD2 in balancing oxygen delivery and red blood cell production.
- At the molecular level, PHD2 is considered the dominant regulator of HIF-1α under normal oxygen tension, whereas PHD1 and PHD3 contribute to fine-tuning hypoxic responses in more tissue-specific or stress-induced contexts. PHD2 itself is regulated by hypoxia: HIF stabilization can upregulate EGLN1 transcription, creating a negative feedback loop to limit HIF activation once oxygen levels are restored. This autoregulatory mechanism prevents excessive or prolonged hypoxia signaling, which could otherwise disrupt vascular and metabolic homeostasis.
- Beyond its canonical role in oxygen sensing, PHD2 has been implicated in other cellular processes. Evidence suggests that PHD2 influences endothelial cell migration, extracellular matrix remodeling, and immune responses. In cancer biology, PHD2 exhibits a complex role: while loss of PHD2 enhances HIF-driven angiogenesis and tumor progression, partial reduction of PHD2 in stromal cells can normalize tumor vasculature and improve oxygenation, paradoxically reducing metastasis and therapy resistance. These dual effects emphasize the context-dependent function of PHD2 in health and disease.
- From a therapeutic perspective, PHD2 has become a major target in drug development. Pharmacological inhibition of PHD2 stabilizes HIF-α and activates hypoxia-responsive genes, a strategy that has been successfully applied to treat anemia associated with chronic kidney disease. Several PHD inhibitors, such as roxadustat, daprodustat, and vadadustat, are designed to inhibit PHD2 activity, leading to endogenous EPO production and improved iron metabolism. Conversely, strategies to enhance or restore PHD2 activity are being explored as potential approaches in oncology, where aberrant HIF stabilization drives tumor angiogenesis and metabolic adaptation.
