Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases

Hypoxia-inducible factors (HIFs) have important roles in ischaemic and inflammatory diseases and strategies aimed at therapeutically modulating hypoxia signalling pathways are gaining considerable attention. Here, Eltzschig and colleagues focus on a set of oxygen-sensing prolyl hydroxylases — which are responsible for marking HIFs for proteasomal degradation — and assess their emerging potential as therapeutic targets. 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.