# VHL / HIF oxygen sensing

Source: https://onco.cc/pathways/hif-vhl/  
OnCo record `hif-vhl` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The VHL/HIF pathway is how cells sense oxygen (the 2019 Nobel Prize). VHL destroys HIF when oxygen is present. Kidney cancers lose VHL, so HIF-2α is permanently on and drives blood vessel growth and proliferation.

## Summary

In normoxia, prolyl hydroxylases (PHD) hydroxylate HIF-α, allowing the VHL E3 ligase to ubiquitinate it for proteasomal degradation. In hypoxia (or with VHL loss in ~90% of clear-cell RCC), HIF-α accumulates, dimerises with HIF-1β (ARNT), and transcribes VEGF, PDGF, GLUT1, CAIX, cyclin D1, and EPO. HIF-2α is the oncogenic paralogue in RCC; belzutifan blocks its dimerisation. CAIX is a PET and radioligand target (89Zr-girentuximab).

## Fields

- Kind: Pathway
- Last checked: 2026-09-04
- Analogy: VHL is the shredder that destroys the 'we are suffocating' memo whenever there is oxygen around. Kidney cancer breaks the shredder, so the memo piles up and the cell keeps ordering new blood vessels and sugar.
- Interventions: Belzutifan (HIF-2α) in VHL disease and RCC, adjuvant with pembrolizumab (2026); VEGF-directed therapy downstream; CAIX-targeted imaging (89Zr-girentuximab) and radioligands in development

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Hypoxia-inducible_factor
- Wikipedia: https://en.wikipedia.org/wiki/Hypoxia-inducible_factor

## Connected records

- cancers: [Pheochromocytoma and paraganglioma (PPGL)](https://onco.cc/cancers/pheochromocytoma-paraganglioma/), [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- targets: [ARNT](https://onco.cc/targets/arnt/), [HIF-1α (HIF1A)](https://onco.cc/targets/hif1a/), [HIF-2α](https://onco.cc/targets/hif2a/), [VEGF / VEGFR](https://onco.cc/targets/vegf/), [VHL](https://onco.cc/targets/vhl/)
- drugs: [Belzutifan](https://onco.cc/drugs/belzutifan/), [Temsirolimus](https://onco.cc/drugs/temsirolimus/)
- technologies: [CAIX PET (89Zr-girentuximab)](https://onco.cc/technologies/caix-pet/)
- people: [William G. Kaelin Jr.](https://onco.cc/people/william-kaelin/)
- ideas: [Soften the tissue that new metastases need in order to grow](https://onco.cc/ideas/idea-bio2-matrix-stiffness-prevention/), [Use a hypoxia scan to pick patients for adenosine-pathway drugs](https://onco.cc/ideas/idea-bio2-hypoxia-guided-adenosine/)
- pathways: [Cancer metabolism](https://onco.cc/pathways/cancer-metabolism/), [Choline metabolism in cancer](https://onco.cc/pathways/choline-metabolism-in-cancer/), [Nutrient competition & metabolic immunosuppression](https://onco.cc/pathways/nutrient-competition-tme/), [Renal cell carcinoma (KEGG map)](https://onco.cc/pathways/renal-cell-carcinoma-signalling/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/), [The angiogenic switch & tumour vessels](https://onco.cc/pathways/angiogenic-switch/), [The pre-metastatic niche](https://onco.cc/pathways/pre-metastatic-niche/), [Ubiquitin-proteasome system & protein homeostasis](https://onco.cc/pathways/ubiquitin-proteasome-system/)
- terms: [Angiogenesis](https://onco.cc/terms/angiogenesis/), [Hallmark: inducing or accessing vasculature](https://onco.cc/terms/inducing-angiogenesis/), [Hallmark: reprogramming cellular metabolism](https://onco.cc/terms/deregulating-cellular-energetics/), [Metabolic theory of cancer: from Warburg to oncometabolites](https://onco.cc/terms/metabolic-theory-of-cancer/), [Von Hippel-Lindau disease](https://onco.cc/terms/vhl-disease/), [Warburg effect](https://onco.cc/terms/warburg-effect/)

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