Category: signaling
Cells sense O2 via PHD (prolyl hydroxylase) enzymes that hydroxylate HIF-α (HIF-1α + HIF-2α) on conserved prolines using O2 + α-ketoglutarate. Normoxia: hydroxylated HIF-α is recognized by VHL E3 ligase → ubiquitinated → proteasome. Hypoxia: PHD has no O2 substrate → HIF-α accumulates → binds HIF-β → nuclear → HRE-driven transcription of EPO, VEGF, glycolytic enzymes (Warburg effect), GLUT1. Tumor angiogenesis + Warburg metabolism = pathological HIF activation. HIF-PHD INHIBITORS (roxadustat, vadadustat, daprodustat) stabilize HIF → endogenous EPO synthesis without rhEPO injection → orally treat CKD anemia (alternative to ESA therapy). Phase 3 + post-marketing safety remains under scrutiny (CV signal in some trials).