HIF prolyl hydroxylase domain (PHD1/2/3)

Class

HIF-PHD inhibitor (oral, for renal anemia — same class as roxadustat)

Pathway

Hypoxia-inducible factor (HIF) stabilization → endogenous erythropoietin production

HIF prolyl hydroxylase domain enzymes (PHD1, PHD2, and PHD3) are oxygen-sensing proteins that regulate the stability of hypoxia-inducible factor (HIF), a transcription factor governing the body's response to low oxygen. Under normal oxygen levels, PHDs chemically tag HIF for destruction. When oxygen is scarce, PHD activity falls, HIF accumulates, and it switches on genes that help cells adapt, including the gene for erythropoietin (EPO), the hormone that stimulates red blood cell production in bone marrow. In chronic kidney disease, the kidneys lose much of their capacity to produce EPO, leading to anemia. Small-molecule PHD inhibitors block these enzymes even under normal oxygen conditions, tricking cells into producing more HIF and, consequently, more endogenous EPO. This offers an oral alternative to injectable recombinant EPO therapies, with the added feature that HIF activation also promotes genes involved in iron absorption and transport, potentially easing the iron-limited red cell production often seen in kidney-related anemia. Because HIF signaling touches many biological processes beyond erythropoiesis, this class of mechanism is studied for renal anemia broadly, spanning both dialysis-dependent and non-dialysis stages of chronic kidney disease.