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HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron
Open accessAbstract
Hypoxia is a hallmark of solid tumors that promotes cell growth, survival, and metastasis and confers resistance to chemo and radiotherapies. Hypoxic responses are largely mediated by the transcription factors hypoxia-inducible factor 1α (HIF-1α) and HIF-2α. Our work demonstrates that HIF-2α is essential for colorectal cancer (CRC) progression. However, targeting hypoxic cells is difficult, and tumors rapidly acquire resistance to inhibitors of HIF-2α. To overcome this limitation, we performed a small molecule screen to identify HIF-2α-dependent vulnerabilities. Several known ferroptosis activators and dimethyl fumarate (DMF), a cell-permeable mitochondrial metabolite derivative, led to selective synthetic lethality in HIF-2α-expressing tumor enteroids. Our work demonstrated that HIF-2α integrated 2 independent forms of cell death via regulation of cellular iron and oxidation. First, activation of HIF-2α upregulated lipid and iron regulatory genes in CRC cells and colon tumors in mice and led to a ferroptosis-susceptible cell state. Second, via an iron-dependent, lipid peroxidation-independent pathway, HIF-2α activation potentiated ROS via irreversible cysteine oxidation and enhanced cell death. Inhibition or knockdown of HIF-2α decreased ROS and resistance to oxidative cell death in vitro and in vivo. Our results demonstrated a mechanistic vulnerability in cancer cells that were dependent on HIF-2α that can be leveraged for CRC treatment.
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“Belzutifan has also demonstrated significant efficacy in heavily pretreated metastatic RCC suggesting that HIF-2α inhibition might also offer an effective treatment for advanced ccRCC [91].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [91]
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“Belzutifan has also demonstrated significant efficacy in heavily pretreated metastatic RCC suggesting that HIF-2α inhibition might also offer an effective treatment for advanced ccRCC [91].”
From Revisiting the HIF switch in the tumor and its immune microenvironment. (2022) · cites this paper as [91]
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Hypoxia-inducible factors: details create a picture. Part II. HIF-2
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“…DFO acts as an iron (Fe 2+ ) chelator, thus inhibiting the function of HIF-PHDs, hypoxia-inducible factor-prolyl hydroxylase domain proteins, and other Fe 2+ , O 2 , and 2-oxogluterate-dependent enzymes that mark HIF, hypoxia-inducible factor, proteins for proteasomal degradation [23,27,28].”
The VCPKMT-VCP-HDAC1 axis inhibits colorectal cancer by conferring sensitivity to ferroptosis
Huang, C., Lin, J., Xu, S., Lv, Y., Chen, J., Cao, J., Xie, D., & Wang, F. (2025) · Cancer Cell International · doi:10.1186/s12935-025-04044-x · Cited by 1
“Ferroptosis activators also induce synthetic lethality in CRC cells that rapidly acquire resistance to hypoxia-inducible factor (HIF)−2α inhibitors [31].”
Research progress on vasculogenic mimicry in colorectal cancer: mechanisms and therapeutic
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“HIF-2α can promote tumor VM formation by regulating VEGFR2 under hypoxic conditions, which is particularly prominent in melanoma [110] and pancreatic carcinoma [34].”
Labile iron pool dynamics do not drive ferroptosis in colorectal cancer cells
Ponnusamy, V., Randall, D. R., Lee, Z. H., Das, N. K., Zhao, L., Buscher, K. A., Solanki, S., Renslo, A. R., Hsu, P. P., & Shah, Y. M. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.111357 · Cited by 2
“Notably, certain cancers, such as CRC, exhibit a strong dependence on iron for growth, and are potentially susceptible to ferroptosis-based therapies (14–17).”
Self-citationFibroblast-specific Gpx4 deletion exacerbates IBD via lipid peroxidation
Zhang, Y., Ying, Y., Huang, W., Rosenfeld, Z. A., El-Derany, M. O., Lee, Z. H., Castillo, C., Oh, T. G., Greenson, J. K., & Shah, Y. M. (2026) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00387.2025 · Cited by 1
Self-citationBelzutifan Attenuates Choroidal Neovascularization by Suppressing the HIF ‐2α/ PAI ‐1 Axis
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“Meanwhile, HIF-2 α increases the expression of perilipin 2 and HILPDA, leading to selective accumulation of PUFAs, heightened oxidative stress, and subsequent ferroptosis [25,26].”
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Lipid droplets as stress-buffering organelles in cancer cell homeostasis
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“Hypoxiacanin fl uence ferroptosis susceptibility through several pathways, including changes in iron handling, lipid metabolism, and antioxidant defense, and GPX4 remains a key regulator of lipid peroxide detoxi fi cation 94,95 .”
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“A recent work has also described that elevated HIF2α induces ROS generation and oxidative cell death in colon cells (34).”
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“Recently, it has been shown that increased HIF-2α activity in CRC primes cells to undergo ferroptosis [84].”
BackgroundStratifying Ferroptosis Sensitivity in Cells and Tissues with PALP
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Enhancement of Breast Cancer Chemotherapy and Radiotherapy Responses by Modulation of Ferroptosis
Al-Zufairi, A. A. M. (2024) · Sheffield Hallam University · doi:10.7190/shu-thesis-00623
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Progress in research of ferroptosis in gastrointestinal tumors
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Endolysosomal cation channel MCOLN as the novel regulator of redox homeostasis
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The Effect of Hypoxia-Inducible Factors Levels in Sera of Babylon Women with Breast Cancer
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Labile iron pool dynamics do not drive ferroptosis potentiation in colorectal cancer cellsPreprint
Ponnusamy, V., Randall, D. R., Lee, Z., Das, N. K., Zhao, L., Buscher, K., Solanki, S. A., Renslo, A. R., Hsu, P. P., & Shah, Y. M. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.01.662602
“Notably, certain cancers, such as colorectal cancer (CRC), exhibit a strong dependence on iron for growth, and are potentially susceptible to ferroptosis-based therapies 14–17 .”
Self-citationLi, L., Li, R., Zhan, W., Zhuo, Z., Zhang, J., Li, Q., Mu, S., Chen, W., Li, L., & He, S. (2025) · The FASEB Journal · doi:10.1096/fj.202501953r
“In CRC research, the expression of EPAS1 can increase the sensitivity of cells to ferroptosis by upregulating the iron transporter DMT1 and ROS levels [36–38].”
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Metadata
- Authors
- Singhal, R., Mitta, S. R., Das, N. K., Kerk, S. A., Sajjakulnukit, P., Solanki, S., Andren, A., Kumar, R., Olive, K. P., Banerjee, R., Lyssiotis, C. A., & Shah, Y. M.
- Affiliations
- U-M Rogel Cancer Center (US)
- University of Michigan (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Shah, Yatrik M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-06-15
- Volume
- 131
- Issue
- 12
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8203462
- OpenAlex
- W3159210359
- Semantic Scholar
- 87392476cf734f17c13d3774c49b2d48506dbe37
- Cited by
- 215
- References
- 67
- Citations by year
- 2026: 36 · 2025: 47 · 2024: 41 · 2023: 43 · 2022: 39 · 2021: 9
- FWCI
- 21.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01CA148828,R01CA245546,R01DK095201,R01CA244931,R35GM130183,P50CA130810,P30CA046592,DK034933,DK097153)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- HIF-2α, colorectal cancer, ferroptosis, oxidative cell death, hypoxia, reactive oxygen species, cysteine oxidation, dimethyl fumarate, synthetic lethality, HIF-2α inhibitor
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Humans, Iron, Mice, Transgenic, Neoplasm Proteins, Oxidation-Reduction, Colorectal Neoplasms, Cell Hypoxia, Gene Expression Regulation, Neoplastic, Cell Death, Reactive Oxygen Species, HT29 Cells, HCT116 Cells, Mice, Basic Helix-Loop-Helix Proteins
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