Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases

Nat Rev Drug Discov. 2014 Nov;13(11):852-69. doi: 10.1038/nrd4422.


Hypoxia-inducible factors (HIFs) are stabilized during adverse inflammatory processes associated with disorders such as inflammatory bowel disease, pathogen infection and acute lung injury, as well as during ischaemia-reperfusion injury. HIF stabilization and hypoxia-induced changes in gene expression have a profound impact on the inflamed tissue microenvironment and on disease outcomes. Although the mechanism that initiates HIF stabilization may vary, the final molecular steps that control HIF stabilization converge on a set of oxygen-sensing prolyl hydroxylases (PHDs) that mark HIFs for proteasomal degradation. PHDs are therefore promising therapeutic targets. In this Review, we discuss the emerging potential and associated challenges of targeting the PHD-HIF pathway for the treatment of inflammatory and ischaemic diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Gene Expression / drug effects
  • Humans
  • Hypoxia / drug therapy*
  • Hypoxia / metabolism
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Ischemia / drug therapy*
  • Ischemia / metabolism
  • Pharmaceutical Preparations / administration & dosage*
  • Prolyl Hydroxylases / metabolism
  • Signal Transduction / drug effects*


  • Basic Helix-Loop-Helix Transcription Factors
  • Pharmaceutical Preparations
  • Prolyl Hydroxylases