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Targeting hypoxia-inducible factors: therapeutic opportunities and challenges

Nature Reviews Drug Discovery volume 23, pages 175–200 (2024)Cite this article

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Abstract

Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that are crucial for adaptation of metazoans to limited oxygen availability. Recently, HIF activation and inhibition have emerged as therapeutic targets in various human diseases. Pharmacologically desirable effects of HIF activation include erythropoiesis stimulation, cellular metabolism optimization during hypoxia and adaptive responses during ischaemia and inflammation. By contrast, HIF inhibition has been explored as a therapy for various cancers, retinal neovascularization and pulmonary hypertension. This Review discusses the biochemical mechanisms that control HIF stabilization and the molecular strategies that can be exploited pharmacologically to activate or inhibit HIFs. In addition, we examine medical conditions that benefit from targeting HIFs, the potential side effects of HIF activation or inhibition and future challenges in this field.

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Fig. 1: Molecular structure of hypoxia-inducible factors.
Fig. 2: Crystal structures of PHD2 and HIF-PHDi complexes and HIF2α–PT2385–PT2977 complexes.
Fig. 3: Potential therapeutic applications of HIF-PHDis in various diseases.
Fig. 4: Potential therapeutic applications of HIF inhibition in various diseases.

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Acknowledgements

H.K.E. is supported by National Institute of Health Grants R01HL154720, R01HL154720-03S1, R01HL165748, R01HL169519, R01DK122796, T32GM135118, Department of Defense Grant W81XWH2110032, and sponsored contract through Akebia Therapeutics. X.Y. is supported by National Institute of Health Grants R01HL155950, R01HL155950-02S1, R01HL169519, Parker B. Francis Fellowship, and sponsored contract through Akebia Therapeutics. W.R. is supported by Natural Science Foundation of Hunan Province Grant 018JJ3736, Young Talent Foundation of Hunan Province Grant 2021RC3034, and 2022 International Anesthesia Research Society Mentored Research Award.

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Authors and Affiliations

  1. Department of Anaesthesiology, Critical Care and Pain Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Xiaoyi Yuan, Wei Ruan & Holger K. Eltzschig

  2. Department of Anaesthesiology, The Second Xiangya Hospital, Central South University, Changsha, China

    Wei Ruan

  3. Department of Emergency Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Bentley Bobrow

  4. Laboratory of Angiogenesis & Vascular Metabolism, Center for Cancer Biology, VIB, Department of Oncology, KU Leuven, Leuven, Belgium

    Peter Carmeliet

  5. Laboratory of Angiogenesis & Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Peter Carmeliet

  6. Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates

    Peter Carmeliet

  7. Outcomes Research Consortium, Cleveland, OH, USA

    Holger K. Eltzschig

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Contributions

X.Y. and W.R. equally researched data for the article, made substantial contribution to discussion of content, wrote the article and reviewed and edited the manuscript before submission. B.B. and P.C. reviewed and edited the article before submission. H.K.E. contributed substantially to conceptualization of the content of the article and reviewed and edited the manuscript before submission.

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Correspondence to Xiaoyi Yuan or Holger K. Eltzschig.

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Competing interests

H.K.E., B.B. and X.Y. received research funding through a contract between Akebia Therapeutics and UTHealth to support a clinical trial on the effect of vadadustat in hospitalized patients with COVID-19 (NCT04478071). Akebia Therapeutics is not involved in conceptualization, design, data collection, analysis, decision to publish or preparation of the manuscript. W.R. and P.C. declare no competing interests.

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Glossary

ADORA2B receptor

A G-protein-coupled receptor that is activated by the signalling molecule adenosine. It has a role in regulating various physiological processes, including inflammation, angiogenesis and immune cell function.

Angiopoietin 1 (ANGPT1) and ANGPT2

Two growth factors that have crucial roles in the regulation of angiogenesis, blood vessel maturation and vascular stability. Whereas ANGPT1 generally promotes vessel stabilization and maturation, ANGPT2 is often associated with vascular destabilization and remodelling, facilitating the actions of other angiogenic factors such as vascular endothelial growth factor.

C-terminal transactivation domain

(C-TAD). A region found at the C terminus of certain transcription factors, including hypoxia-inducible factors, which is responsible for activating target gene transcription by recruiting coactivators and other components of the transcription machinery to the target gene promoter.

Erythropoiesis-stimulating agents

(ESAs). A group of medications that mimic the effects of erythropoietin, promoting the production of red blood cells in the bone marrow and used to treat conditions such as anaemia.

Erythropoietin

(EPO). A glycoprotein cytokine primarily produced by the kidneys in response to cellular hypoxia. Its main biological function is to stimulate erythropoiesis in the bone marrow.

Factor inhibiting HIF

(FIH). Also known as asparaginyl hydroxylase; hydroxylates a specific asparagine residue in the C-terminal transactivation domain of hypoxia-inducible factors (HIFs). This modification inhibits the interaction between HIFs and the transcriptional coactivators histone acetyltransferase p300 and cyclic adenosine monophosphate response element binding protein (CREB) binding protein (CBP), thereby reducing HIF-mediated gene transcription.

Hepcidin

Hepcidin is a liver-produced peptide hormone that regulates iron metabolism by inhibiting iron release from cells and decreasing dietary iron absorption, thereby maintaining iron homeostasis in the body.

Hypoxia-responsive elements

(HREs). Short DNA sequences found in the regulatory regions of hypoxia-inducible genes, which allow for their transcriptional activation by hypoxia-inducible factors when cellular oxygen levels are low, thereby promoting cellular adaptation to hypoxic conditions.

Lipopolysaccharide (LPS) treatment

The experimental administration of LPSs, molecules from the outer membrane of Gram-negative bacteria, to induce an inflammatory response in the lungs, simulating conditions such as acute respiratory distress syndrome for research purposes.

Locked nucleic acid

A modified RNA nucleotide in which the ribose ring is ‘locked’ by a methylene bridge connecting the 2′-O atom with the 4′-C atom, which enhances its thermal stability and its affinity for complementary RNA and DNA strands, making it a valuable tool in molecular biology and medical research, particularly in the fields of genomics and therapeutics.

Pacak–Zhuang syndrome

A rare condition characterized by the presence of paragangliomas, often in the head and neck region, and associated with somatic mutations in the HIF2A gene, which encodes hypoxia-inducible factor 2α. This syndrome may also be accompanied by polycythaemia and, in some cases, duodenal somatostatinomas.

Polycythaemia

A condition characterized by an increased number of red blood cells in the bloodstream, which can thicken the blood, slow its flow and increase the risk of clotting. It can be a primary disease owing to mutations in the bone marrow cells, referred to as polycythaemia vera, or secondary, often as a response to hypoxia or certain tumours.

Respiratory bursts

Rapid increases in cellular oxygen consumption, primarily in immune cells such as neutrophils and macrophages, that lead to the production of reactive oxygen species to combat pathogens during an immune response.

Von Hippel–Lindau protein

(pVHL). A tumour suppressor protein involved in regulation of cellular responses to oxygen levels by targeting hypoxia-inducible factors for degradation under normal oxygen conditions.

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Yuan, X., Ruan, W., Bobrow, B. et al. Targeting hypoxia-inducible factors: therapeutic opportunities and challenges. Nat Rev Drug Discov 23, 175–200 (2024). https://doi.org/10.1038/s41573-023-00848-6

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