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Cited by 384Cancer, Hypoxia, and MetabolismErythropoietin and Anemia TreatmentAcute Kidney Injury Research

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Hypoxia signaling in human diseases and therapeutic targets

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Lee, Jae W., Ko, Junsuk, Ju, Cynthia, Eltzschig, Holger K.·2019·Experimental & Molecular Medicine
DOI 10.1038/s12276-019-0235-1PMC PMC6586801
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Abstract

Since the discovery of hypoxia-inducible factor (HIF), numerous studies on the hypoxia signaling pathway have been performed. The role of HIF stabilization during hypoxia has been extended from the induction of a single gene erythropoietin to the upregulation of a couple of hundred downstream targets, which demonstrates the complexity and importance of the HIF signaling pathway. Accordingly, HIF and its downstream targets are emerging as novel therapeutic options to treat various organ injuries. In this review, we discuss the current understanding of HIF signaling in four different organ systems, including the heart, lung, liver, and kidney. We also discuss the divergent roles of HIF in acute and chronic disease conditions and their revealed functions. Finally, we introduce some of the efforts that are being performed to translate our current knowledge in hypoxia signaling to clinical medicine. A protein family that plays diverse roles in acute and chronic hypoxia (low oxygen) may prove valuable in developing novel therapies for different diseases. Hypoxia, the short- or long-term depletion of oxygen in cells, tissues and organs, is involved in many disease conditions. Holger Eltzschig at the McGovern Medical School in Houston, USA, and co-workers reviewed research into the roles of a key hypoxia regulator, the hypoxia-inducible factor (HIF) protein group, in diseases affecting the heart, lung, liver and kidneys. HIF protein activity is often beneficial in acute conditions such as myocardial ischemia, sending signals to protect cells and increasing tissue tolerance to hypoxia. However, during chronic hypoxia, HIF signaling may contribute to the progression of disease, for example in pulmonary fibrosis. HIF stabilizers and HIF-induced targets as drugs could prove valuable in future treatments.

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  • Several hypoxia mimetics are approved for clinical use.

    “several such agents are now approved for clinical use (reviewed in Refs. [[34], [35], [36], [37]])”

    From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [34]

    In “Potential targets for therapeutic intervention” (page unavailable), the review says the named PHD inhibitors vadadustat, roxadustat, and daprodustat were being tested in clinical trials, not that several hypoxia mimetics were approved for clinical use. It notes that sevoflurane is commonly used as an anesthetic, but says its proposed HIF-mediated protective use was also undergoing trials. (LLM, conf=0.86)

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Metadata

Authors
Lee, J. W., Ko, J., Ju, C., & Eltzschig, H. K.
Affiliations
  • Kyung Hee University (KR)
  • The University of Texas Health Science Center at Houston (US)
Corresponding author
Eltzschig, Holger K.
ORCID
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2019-06
Volume
51
Issue
6
Pages
1-13
ISSN
  • 1226-3613 (ISSN-L)
  • 2092-6413
DOI
10.1038/s12276-019-0235-1
PMC
PMC6586801
OpenAlex
W2950944645
Cited by
384
References
102
Citations by year
2026: 19 · 2025: 31 · 2024: 61 · 2023: 62 · 2022: 77 · 2021: 90 · 2020: 43 · 2019: 1
FWCI
5.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Experimental & Molecular Medicine (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • American Heart Association (18PRE33960076)
  • National Institute on Alcohol Abuse and Alcoholism (R21AA024636, U01AA021723)
  • National Heart, Lung, and Blood Institute (R01HL119837, R01HL133900, P01HL114457, R01HL109233)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK109574, R01DK097075)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
Keywords
hypoxia signaling, hypoxia-inducible factor, HIF stabilization, erythropoietin, myocardial ischemia, pulmonary fibrosis, liver disease, kidney disease, chronic hypoxia, acute hypoxia, HIF stabilizers, therapeutic target, organ damage
MeSH terms
Animals, Hypoxia, Heart Diseases, Humans, Kidney Diseases, Liver Diseases, Lung Diseases, Signal Transduction, Hypoxia-Inducible Factor 1

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