Oxygen is essential for cellular respiration that produces ATP, yet the concentration inside tissues fluctuates during exercise, bleeding or high-altitude exposure. Kaelin, Ratcliffe and Semenza uncovered the pathway that allows cells to detect such changes and adjust gene expression accordingly. The central player they studied, HIF-1α, is degraded when oxygen is abundant but becomes stable and accumulates in the nucleus under hypoxia. Key enzymes—prolyl hydroxylases (PHDs) and the VHL protein—use oxygen to tag HIF-1α for destruction via the ubiquitin-proteasome system. Once activated, HIF turns on genes such as erythropoietin, boosting red-blood-cell production, and also drives angiogenesis and shifts glucose metabolism. The hypoxic response is vital for endurance sports, fetal development and even cancer cell growth in poorly oxygenated regions. These discoveries directly enabled new anaemia drugs (PHD inhibitors) and inspire anti-cancer agents that block HIF activity, demonstrating wide societal impact. The work is a textbook example of how organisms reprogram gene usage to meet environmental challenges, bridging biology, chemistry and medicine.

Hypoxia-inducible factors (HIFs) are bHLH-PAS transcription factors composed of an oxygen-regulated α-subunit (HIF-1α, HIF-2α/EPAS1, etc.) and a constitutively expressed β-subunit (ARNT). Under normoxia, prolyl hydroxylases PHD1–3 hydroxylate specific prolines within the oxygen-dependent degradation domain of HIF-α, enabling recognition by the VHL E3 ubiquitin ligase complex and proteasomal degradation. Hypoxia limits O2 availability, stalls hydroxylation and stabilises HIF-α, which translocates into the nucleus and dimerises with ARNT. In parallel, inhibition of FIH-1–mediated Asn803 hydroxylation restores interaction with the p300/CBP co-activator, enhancing transcription. More than 300 HIF target genes—including EPO, VEGF, GLUT1 and LDHA—drive erythropoiesis, angiogenesis and metabolic reprogramming. Kaelin approached the pathway through VHL disease, Ratcliffe linked oxygen sensing to the VHL–HIF axis and Semenza isolated and cloned HIF itself. Their insights enabled clinical innovations such as PHD inhibitors (roxadustat) for anaemia and HIF-2α inhibitors (belzutifan) for VHL-associated renal carcinoma. The pathway explains key aspects of myocardial ischaemia, stroke, chronic inflammation and the tumour micro-environment, making it a versatile drug target. It also informs research on high-altitude adaptation, developmental morphogenesis and immunometabolism, forming a paradigm in molecular physiology. Methodologically, the studies integrated EMSA/ChIP for DNA binding, mass spectrometry for PTM mapping, knockout mouse models and molecular pathology of clinical samples.

Prolyl-4-hydroxylation of HIF-α is catalysed by Fe(II)/2-oxoglutarate-dependent PHD1–3 with a Km(O2) of ~230–250 µM, enabling kinetic sensing within physiological pO2. VHL engages the elongin B/C–CUL2–RBX1 complex via a SOCS-box-like motif and installs K48-linked ubiquitin chains on HIF-α, reducing its half-life to about five minutes. FIH-1 hydroxylates Asn803, blocking interaction with the p300 CH1 domain; because its Km(O2) exceeds that of PHDs, it provides a second-tier oxygen gauge. Ratcliffe’s group solved the crystal structure of a hydroxy-proline-containing HIF-α peptide bound to VHL, revealing a hydrogen-bond network with VHL Tyr98/Ser111 that underpins high affinity. In tumours, the oncometabolite 2-hydroxyglutarate competitively inhibits PHD/FIH, generating pseudohypoxia that drives malignancy. Phase-III PHD inhibitors raise concerns about off-target effects, but RNA-seq indicates the induced transcriptome is largely confined to canonical HIF targets. The HIF-2α inhibitor belzutifan occupies the PAS-B cavity to block dimerisation, yet resistance via a G323E mutation has emerged. Future work must elucidate crosstalk with metabolic sensors (mTOR, AMPK) and hypoxia-induced ribosome remodelling that links oxygen sensing to translational control.