The DOI matches its Crossref record; 317 of the 317 references it cites were found in a registry or an index.
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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“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]
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“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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Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535
The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
Maxwell, P. H., Wiesener, M. S., Chang, G.-W., Clifford, S. C., Vaux, E. C., Cockman, M. E., Wykoff, C. C., Pugh, C. W., Maher, E. R., & Ratcliffe, P. J. (1999) · Nature · doi:10.1038/20459 · Cited by 5,180
Targeting Hypoxia-Inducible Factors for the Treatment of Anemia in Chronic Kidney Disease Patients
Locatelli, F., Fishbane, S. N., Block, G. A., & Macdougall, I. C. (2017) · American Journal of Nephrology · doi:10.1159/000455166 · Cited by 4,836
HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735
Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1
Forsythe, J. A., Jiang, B.-H., Iyer, N. V., Agani, F., Leung, S. W., Koos, R. D., & Semenza, G. L. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.9.4604 · Cited by 3,981 · cited 1×
“Similarly, HIFαs are crucial for the induction of tumour growth factors, such as vascular endothelial growth factor (VEGF) 302,303 , via HIF2α in renal cell carcinoma 58 .”
Comprehensive molecular characterization of clear cell renal cell carcinoma
The Cancer Genome Atlas Research Network (2013) · Nature · doi:10.1038/nature12222 · Cited by 3,485
Ischemia and reperfusion—from mechanism to translation
Eltzschig, H. K., & Eckle, T. D. L. G. (2011) · Nature Medicine · doi:10.1038/nm.2507 · Cited by 3,468
Self-citationEpstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333
Semenza, G. L., & Wang, G. L. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.12.5447 · Cited by 2,617
Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis
Carmeliet, P., Dor, Y., Herbert, J.-M., Fukumura, D., Brusselmans, K., Dewerchin, M., Neeman, M., Bono, F., Abramovitch, R., Maxwell, P., et al. (1998) · Nature · doi:10.1038/28867 · Cited by 2,502
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Research works printed but not linked: 2
- Pelosci, A. LITESPARK-005 trial reveals PFS benefit of belzutifan in advanced RCC. Cancer Network, Home of the Journal ONCOLOGY (23 August 2023).
- Tang, H. et al. Endothelial HIF-2alpha contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. Am. J. Physiol. Lung Cell Mol. Physiol. 314, L256–L275 (2018).
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Glaviano, A., Lau, H., Carter, L. M., Lee, E. H. C., Lam, H. Y., Okina, E., Tan, D. J. J., Tan, W., Ang, H. L., Carbone, D., et al. (2025) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01634-6 · Cited by 169
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Jin, Y., Wu, O., Chen, Q., Chen, L., Zhang, Z., Tian, H., Zhou, H., Zhang, K., Gao, J., Wang, X., et al. (2024) · Advanced Science · doi:10.1002/advs.202404275 · Cited by 82
Metadata
- 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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