Egl-9 family hypoxia inducible factor 3 (EGLN3) (EGLN3)

Egl-9 family hypoxia inducible factor 3 (EGLN3), also known as Prolyl hydroxylase domain-containing protein 3 (PHD3), is a member of the EGLN family of 2-oxoglutarate-dependent dioxygenases that serves as a critical oxygen sensor in mammalian cells (UniProt: Q9H6Z9). Its primary biological function is the prolyl hydroxylation of Hypoxia-Inducible Factor (HIF) alpha subunits, a modification that targets HIF for polyubiquitination by the von Hippel-Lindau (VHL) complex and subsequent degradation by the 26S proteasome (PubMed: 11595184). Under hypoxic conditions, the catalytic activity of EGLN3 is inhibited, leading to the stabilization and accumulation of HIF, which then drives the expression of genes such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF) to facilitate adaptation to low oxygen (NCBI Gene: 112399). In clinical practice, EGLN3 is targeted alongside its isoforms (EGLN1 and EGLN2) by a class of drugs known as HIF-PHD inhibitors, including Roxadustat and Daprodustat, which are approved for treating anemia in chronic kidney disease patients (PubMed: 31339672). Beyond erythropoiesis, EGLN3 has been implicated in regulating cell death and metabolic reprogramming in various cancers, where its expression levels often correlate with tumor progression or suppression depending on the tissue context (PubMed: 23064224).

Other names

Prolyl hydroxylase domain-containing protein 3PHD3HIF-prolyl hydroxylase 3HPH-1HPH-3Hypoxia-inducible factor prolyl hydroxylase 3

EGLN3 inhibitors act as 2-oxoglutarate analogues that competitively bind to the active site of the enzyme, thereby preventing the hydroxylation of HIF-alpha subunits (PubMed: 30635230). This stabilization of HIF-alpha mimics the physiological response to hypoxia, promoting the transcription of the EPO gene in the kidneys and liver, which increases red blood cell production (PubMed: 31339672).