- Prolyl hydroxylase domain protein 1 (PHD1), also known as EGLN2 (Egl-9 homolog 2), is one of the three major isoforms of the oxygen-sensing prolyl hydroxylases that regulate the stability of hypoxia-inducible factors (HIFs).
- Like its family members PHD2 and PHD3, PHD1 is an Fe²⁺-, 2-oxoglutarate–, and oxygen-dependent dioxygenase that hydroxylates conserved proline residues in the oxygen-dependent degradation domain (ODD) of HIF-α subunits under normoxic conditions. This post-translational modification creates a recognition site for the von Hippel–Lindau (pVHL) protein, which in turn targets HIF-α for ubiquitination and proteasomal degradation. Thus, PHD1 is part of the molecular machinery that couples oxygen availability to the transcriptional activity of HIF-regulated genes.
- Among the PHD isoforms, PHD1 has a more specialized expression pattern and function. It is highly expressed in metabolic tissues, particularly the testes, liver, and skeletal muscle, where it plays an important role in regulating energy metabolism and cellular adaptation to oxygen fluctuations. Studies have shown that PHD1 is involved in controlling mitochondrial function, oxidative phosphorylation, and the balance between aerobic and anaerobic energy production. In skeletal muscle, for instance, PHD1 deficiency has been linked to increased hypoxia tolerance, as reduced hydroxylation activity allows HIF-α stabilization and promotes a metabolic shift toward glycolysis, conserving oxygen during low availability.
- Unlike PHD2, which is the dominant regulator of HIF stability in most cell types, PHD1 is not indispensable for embryonic development but contributes to fine-tuning the hypoxic response in specific physiological contexts. Experimental evidence suggests that PHD1 modulates cell proliferation, metabolism, and stress resistance, particularly under conditions of nutrient limitation or hypoxia. Additionally, PHD1 appears to have HIF-independent roles, such as regulating cell cycle progression and apoptosis, though these mechanisms are still under active investigation.
- Clinically, alterations in PHD1 function have been associated with several pathophysiological conditions. In cancer, downregulation of PHD1 has been observed in some tumor types, potentially enhancing HIF activity and promoting tumor survival in hypoxic microenvironments. On the other hand, experimental inactivation of PHD1 has shown protective effects in ischemia–reperfusion injury by preconditioning tissues to hypoxia and reducing oxidative stress. These dual roles highlight the context-dependent nature of PHD1 function, where its modulation can either promote disease progression or confer cytoprotection depending on the physiological or pathological setting.
- Overall, PHD1 is a critical oxygen-sensing enzyme that refines the hypoxic response beyond the broad regulatory functions of PHD2. Its specialized roles in metabolism, tissue-specific oxygen adaptation, and stress resistance make it a key player in both normal physiology and disease. As research into prolyl hydroxylase inhibitors (HIF-PHIs) expands, understanding the distinct contributions of PHD1 may open new therapeutic avenues in metabolic disorders, ischemic diseases, and oncology.
