The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
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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Citations
Cites
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.021 · Cited by 7,695
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212
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
Hypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645
CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy
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Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors
Rawla, P., Sunkara, T., & Barsouk, A. A. (2019) · Gastroenterology Review · doi:10.5114/pg.2018.81072 · Cited by 2,477
HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression
Keith, B., Johnson, R. S., & Simon, M. C. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3183 · Cited by 1,693
Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy
Semenza, G. L. (2012) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2012.01.005 · Cited by 1,514
General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia.
Wang, G. L., & Semenza, G. L. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.9.4304 · Cited by 1,468
Cited by
Sorted by citations
Items 201–215 of 215
Synthetic lethality by poly (ADP-ribose) polymerase inhibitors
Perween, S., Patidar, V., Kumar, S., Dahiya, S., & Singh, R. K. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-44041-0.00015-5
The Interaction Between Iron and Selenium Affects Ferroptosis in Colorectal Cancer
陶福林, He, M., & Dai, Y. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27093963
“…has become an especially important area of study because CRC cells display distinctive metabolic features, including elevated intracellular iron content, increased ROS production, and disordered lipid metabolism, all of which may render them particularly vulnerable to ferroptotic death [1,7].”
Jiao, G., Baracaldo-Lancheros, L. F., Dhiman, A., Ferreira, C. R., & Dykhuizen, E. C. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.02.722429
Yu, Y., Ma, B., Liu, Y., Wang, Z., Chen, J., Li, X., Sun, S., & Bao, S. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102228
Wang, Y.-Y., Yang, H., Wang, N., & Ding, L. (2026) · World Journal of Clinical Oncology · doi:10.5306/wjco.120414
Wu, D., Huang, X., Zhang, J., Zhang, D., Peng, S., Tang, W., & Li, H. (2026) · Materials & Design · doi:10.1016/j.matdes.2026.116386
HIFs: The central drivers of tumors and their role as molecular switches in targeted therapy?
Peng, Y., Che, Y., Zhao, Y., Wang, Z., Pei, Z., Hu, Y., Yin, Y., Pan, X., Hu, X., Wei, M., et al. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.06.040
“In contrast, HIF-2 α sensitizes CRC and ccRCC to ferroptosis, either by cooperating with ferroptosis activators ( e.g. , Erastin) or by upregulating hypoxia-inducible lipid droplet-associated protein (HILPDA) to promote the accumulation of polyunsaturated fatty acids (PUFAs) 84,85 .”
Sitholumusa, M. U. I., Deng, S., Li, Z., Zhang, Y. F., Li, M., Chen, B., Zhao, J., Sun, C., & Kai, G. (2026) · Clinical Traditional Medicine and Pharmacology · doi:10.1016/j.ctmp.2026.200295
Zhang, J., Xie, S., & Wang, Y. (2026) · Biomedicines · doi:10.3390/biomedicines14081712
“In the hypoxic TME, HIF-2 α regulates HILPDA and PLIN2, thereby modulating oxidized lipid accumulation, ferroptosis-related responses, and tumor cell behavior [105].”
Deciphering the colorectal tumor microenvironment: Interactions and targets for effective therapy
Zhao, J., Shi, C., Du, Y., Li, G., & Yan, C. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118303
O 2 -sensing and HIF regulation: from oxygen homeostasis to tumor-associated immune responses
Schneider, V., Fandrey, J., & Winning, S. (2026) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00185.2026
Neural–metabolic crosstalk governing cell death and therapy resistance in tumors
Yan, Y., Sun, H., Liu, Z., Bhol, C. S., Sethi, G., Xue, W., & Li, L. (2026) · Pharmacological Research · doi:10.1016/j.phrs.2026.108442
MCUB restricts mitochondrial calcium to support metabolic adaptation and homeostasis in glioblastoma
Sun, N., Sun, P., Xuan, F., Zhong, J., Ma, W., Song, Y., Xuan, H., Yu, D., Sun, Z., Zhao, Y., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.118036
Ullah, M. F. (2026) · Medical Oncology · doi:10.1007/s12032-026-03432-1
“The HIF/TFR1 axis represents a critical control point: HIF upregulates iron uptake yet simultaneously activates iron storage proteins that override pro-ferroptotic signals [51 ].”
Pan, Z., Han, J. R., Naowarojna, N., Graham, E. T., Roth, J. A., Wang, W., Xie, G., Wang, X., Li, H., & Zou, Y. (2026) · ACS Chemical Biology · doi:10.1021/acschembio.6c00581
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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