Cited by 245Cancer, Hypoxia, and MetabolismErythropoietin and Anemia TreatmentAngiogenesis and VEGF in Cancer

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Targeting hypoxia-inducible factors: therapeutic opportunities and challenges

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Yuan, Xiaoyi, Ruan, Wei, Bobrow, Bentley, Carmeliet, Peter, Eltzschig, Holger K.·2024·Nature Reviews Drug Discovery

DOI 10.1038/s41573-023-00848-6PMC PMC12337356

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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. This Review discusses the mechanisms that regulate stabilization of hypoxia-inducible factors (HIFs), and the pharmacological strategies to activate or inhibit HIFs in diseases such as ischaemia, inflammation, cancer, retinal neovascularization and pulmonary hypertension.

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See all 245

Authors: Yuan, X., Ruan, W., Bobrow, B., Carmeliet, P., & Eltzschig, H. K.
Affiliations: The University of Texas Health Science Center at Houston (US)
Central South University (CN)
Khalifa University of Science and Technology (AE)
Outcomes Research Consortium (US)
Corresponding author: Yuan, Xiaoyi
Eltzschig, Holger K.
ORCID: Yuan, Xiaoyi
Ruan, Wei
Carmeliet, Peter
Eltzschig, Holger K.
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2023-12-20
Volume: 23
Issue: 3
Pages: 175-200
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/s41573-023-00848-6
PMC: PMC12337356
OpenAlex: W4390038502
Cited by: 245
References: 317
Citations by year: 2026: 100 · 2025: 96 · 2024: 48 · 2023: 1
FWCI: 7.73
Type: journal article
Language: en
Open access: green
pure.au.dk
Licence: other-oa
www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Reviews Drug Discovery (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Lirias (submittedVersion, other-oa)
Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders: U.S. Department of Defense (W81XWH2110032)
Akebia Therapeutics
National Institutes of Health
National Heart, Lung, and Blood Institute (R01HL154720, R01HL165748, R01HL169519, R01HL155950)
National Institute of General Medical Sciences (T32GM135118)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK122796)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords: hypoxia-inducible factor, HIF stabilization, HIF activation, HIF inhibition, oxygen sensing, erythropoiesis, ischemia, inflammation, cancer therapy, retinal neovascularization, pulmonary hypertension, pharmacological targeting, adverse effects
MeSH terms: Hypoxia, Humans, Neoplasms, Oxygen, Transcription Factors, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins

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Targeting hypoxia-inducible factors: therapeutic opportunities and challenges

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