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The effect of HIF on metabolism and immunity
Open accessAbstract
Cellular hypoxia occurs when the demand for sufficient molecular oxygen needed to produce the levels of ATP required to perform physiological functions exceeds the vascular supply, thereby leading to a state of oxygen depletion with the associated risk of bioenergetic crisis. To protect against the threat of hypoxia, eukaryotic cells have evolved the capacity to elicit oxygen-sensitive adaptive transcriptional responses driven primarily (although not exclusively) by the hypoxia-inducible factor (HIF) pathway. In addition to the canonical regulation of HIF by oxygen-dependent hydroxylases, multiple other input signals, including gasotransmitters, non-coding RNAs, histone modifiers and post-translational modifications, modulate the nature of the HIF response in discreet cell types and contexts. Activation of HIF induces various effector pathways that mitigate the effects of hypoxia, including metabolic reprogramming and the production of erythropoietin. Drugs that target the HIF pathway to induce erythropoietin production are now approved for the treatment of chronic kidney disease-related anaemia. However, HIF-dependent changes in cell metabolism also have profound implications for functional responses in innate and adaptive immune cells, and thereby heavily influence immunity and the inflammatory response. Preclinical studies indicate a potential use of HIF therapeutics to treat inflammatory diseases, such as inflammatory bowel disease. Understanding the links between HIF, cellular metabolism and immunity is key to unlocking the full therapeutic potential of drugs that target the HIF pathway.
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“Under hypoxic conditions, where oxygen is unavailable for the hydroxylation reaction, HIF-1α accumulates and forms a dimer with the oxygen-independent ARNT [4].”
From Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition (2025) · cites this paper as [4]
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“A central cellular response to hypoxia and HIF activation is metabolic reprogramming to favor energy-generating pathways that do not require oxygen; the best characterized of which, is the switch from oxidative phosphorylation in the mitochondria (a process that utilizes ~90% of available oxygen), to anerobic glycolysis, thus preserving cellular bioenergetics during periods of oxygen deprivation (”
From The HIF Axes in Cancer - Angiogenesis, Metabolism and Immune-Modulation (2025) · cites this paper as [36]
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Metadata
- Authors
- Taylor, C. T., & Scholz, C. C.
- Affiliations
- University College Dublin (IE)
- University of Zurich (CH)
- Corresponding author
- Taylor, Cormac T.
- Venue
- Nature Reviews Nephrology
- Published
- 2022-06-20
- Volume
- 18
- Issue
- 9
- Pages
- 573-587
- ISSN
- 1745-8323 (ISSN-L)
- 1759-5061
- 1759-507X
- PMC
- PMC9208707
- OpenAlex
- W4283204847
- Cited by
- 517
- References
- 206
- Citations by year
- 2026: 106 · 2025: 186 · 2024: 143 · 2023: 77 · 2022: 5
- FWCI
- 12.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Reviews Nephrology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- hypoxia-inducible factor, cellular hypoxia, cellular metabolism, immune cell function, metabolic reprogramming, erythropoietin, gasotransmitters, non-coding RNA, histone modifiers, post-translational modification, inflammatory bowel disease, inflammation, innate and adaptive immunity
- MeSH terms
- Hypoxia, Erythropoietin, Humans, Kidney, Oxygen, Cell Hypoxia
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