Targeting hypoxia-inducible factors: therapeutic opportunities and challenges
Open accessAbstract
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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Adverse events with HIF-targeted agents are mechanistically informative and context-dependent, supporting patient selection, biomarker-guided monitoring, and agent-specific risk mitigation during prolonged therapy.
“Overall, adverse events with HIF-targeted agents are mechanistically informative and context-dependent, supporting patient selection, biomarker-guided monitoring, and agent-specific risk mitigation during prolonged therapy [37].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [37]
The most frequent on-target toxicity with HIF-2 inhibitors (PT2385; belzutifan) is anemia from suppression of renal/hepatic erythropoietin.
“The most frequent on-target toxicity with HIF-2 inhibitors (PT2385; belzutifan) is anemia from suppression of renal/hepatic erythropoietin.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [37]
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- 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.
- Venue
- Nature Reviews Drug Discovery
- Published
- 2023-12-20
- Volume
- 23
- Issue
- 3
- Pages
- 175-200
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- 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
- 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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