Egl nine homolog 2 (EGLN2) (EGLN2)

Egl nine homolog 2 (EGLN2), also known as Prolyl hydroxylase domain-containing protein 1 (PHD1), is a key oxygen-sensing enzyme that regulates the stability of hypoxia-inducible factors (HIFs) [1, 2]. Under normoxic conditions, EGLN2 hydroxylates specific proline residues on HIF-alpha subunits, marking them for proteasomal degradation via the von Hippel-Lindau (VHL) ubiquitination complex [1, 6]. When oxygen levels are low, EGLN2 activity is inhibited, allowing HIF to accumulate and activate the transcription of genes involved in erythropoiesis, angiogenesis, and metabolic adaptation [3, 6]. Beyond its role in oxygen sensing, EGLN2 is involved in estrogen receptor signaling, mitochondrial function, and the regulation of NF-kappa-B and cell cycle pathways [4, 13]. In clinical medicine, EGLN2 is a therapeutic target for treating anemia associated with chronic kidney disease through the use of pan-PHD inhibitors such as Roxadustat and Vadadustat [2, 6]. These drugs stabilize HIF-alpha, leading to increased endogenous erythropoietin production and improved iron metabolism [6]. EGLN2 is also being investigated for its role in cancer progression, where it can act as either a tumor promoter or suppressor depending on the context, and for its potential as a neuroprotective target in diseases like amyotrophic lateral sclerosis (ALS) [11, 14]. Safety concerns associated with targeting this enzyme include the risk of polycythemia, thromboembolic events, and the potential for promoting tumor growth due to sustained HIF stabilization [2, 6].

Other names

PHD1HPH-1HPH-3HIF-PH1EIT6Prolyl hydroxylase domain-containing protein 1Egl-9 family hypoxia inducible factor 2

Inhibition of prolyl hydroxylase activity to prevent the degradation of HIF-alpha subunits, leading to their stabilization and the subsequent activation of genes involved in erythropoiesis and angiogenesis.