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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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InfluentialKalyanaraman, B. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102497 · Cited by 128
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Prospective Application of Ferroptosis in Hypoxic Cells for Tumor Radiotherapy
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“In addition, many other researchers found that radiotherapy might affect ferroptosis by mediating the expression of iron metabolism-related proteins such as iron ion-related carriers like ferritin, FPN, regulatory iron regulators, membrane iron transport auxiliary protein (Hephaestin) and copper cyanobacteria by media…”
BackgroundFerroptosis: Biology and Role in Gastrointestinal Disease
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“[62] created tamoxifen-inducible HIF-2a expressing murine intestinal tumors to identify HIF-2a dependence and vulnerability, and examined cell proliferation under anticancer drug treatment, including ferroptosis-inducing small molecules.”
BackgroundMycotoxins and cellular senescence: the impact of oxidative stress, hypoxia, and immunosuppression
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Sulfide oxidation promotes hypoxic angiogenesis and neovascularization
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“As the major transcriptional regulator of cellular iron levels, HIF-2α enhances the vulnerability of the proteome to oxidative damage with the existence of DMF and promotes ferroptosis [76].”
BackgroundHIF2α activation and mitochondrial deficit due to iron chelation cause retinal atrophy
Kong, Y., Liu, P., Li, Y., Nolan, N. D., Quinn, P. M. J., Hsu, C., Jenny, L. A., Zhao, J., Cui, X., Chang, Y., et al. (2023) · EMBO Molecular Medicine · doi:10.15252/emmm.202216525 · Cited by 27
“It incurs a “ferroptosis-like” cell fate and potentiates cysteine oxidation to elevate ROS (Mastrogiannaki et al, 2009; Singhal et al, 2021), which corroborates our observation in the DFO-treated RPE.”
BackgroundFerroptosis-related signaling pathways in cancer drug resistance
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“…drugs targeting the SREBP pathway or MED15 in ccRCC. HIF-2 α is the most critical oncogene in ccRCC and is involved in angiogenesis and multiple other processes, including the cell cycle, cell proliferation, tumor metastasis, resistance to oxidative stress and tumor glucose metabolism [10, 26, 51].”
Regulation of the HIF switch in human endothelial and cancer cells
Slawski, J., Jaśkiewicz, M., Barton, A., Kozioł, S., Collawn, J. F., & Bartoszewski, R. (2024) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2024.151386 · Cited by 26
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“The activation of hypoxia-inducible factor 2α (HIF-2α) is one of the ferroptosis-associated features, potentiating oxidative cell death in CRC cells (Singhal et al., 2021).”
BackgroundXiao, R., Zhou, W., Peng, J., Cai, S., Xie, J., Liao, W., Li, S., Ding, K., & He, F. (2025) · Glycoscience & Therapy · doi:10.1016/j.glycos.2025.100003 · Cited by 25
Dong, H., Zhang, C., Shi, D., Xiao, X., Chen, X., Zeng, Y., Li, X., & Xie, R. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2022.11.010 · Cited by 25
“, 2022), colorectal cancer (Singhal et al., 2021) and mouse testes (Wu et al.”
BackgroundNovel Approaches with HIF-2α Targeted Therapies in Metastatic Renal Cell Carcinoma
Nguyen, C. B., Oh, E., Bahar, P., Vaishampayan, U. N., Else, T., & Alva, A. S. (2024) · Cancers · doi:10.3390/cancers16030601 · Cited by 26
Recent progress of ferroptosis in cancers and drug discovery
Wang, X., Ren, X., Lin, X., Li, Q., Zhang, Y., Deng, J., Chen, B., Ru, G., Luo, Y., & Lin, N. (2024) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2024.100939 · Cited by 26
“OTUD1 and HIF-2 α increased intracellular ROS production, promoting ferroptosis [ 92 ].”
BackgroundWu, M., Peng, X., Zhang, M., Guo, H. M., & Xie, H.-T. (2025) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.12.050 · Cited by 25
Mechanism and application of ferroptosis in colorectal cancer
Liu, Y., Zhang, Y., Zhang, Y., & Fan, Z. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.114102 · Cited by 24
Rabitha, R., Shivani, S., Yahya, S., & Sudhandiran, G. (2023) · World Journal of Gastroenterology · doi:10.3748/wjg.v29.i16.2433 · Cited by 24
DeAngelo, S. L., Zhao, L., Dziechciarz, S., Shin, M., Solanki, S. A., Balia, A., El-Derany, M. O., Castillo, C., Qin, Y., Das, N. K., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-24-3478 · Cited by 39
Self-citationChen, X., Tu, J., Ma, L., Huang, Y., Yang, C., & Yuan, X. (2022) · International Journal of General Medicine · doi:10.2147/ijgm.s354682 · Cited by 23
The putative role of ferroptosis in gastric cancer: a review
Wang, L., & Wang, H. (2023) · European Journal of Cancer Prevention · doi:10.1097/cej.0000000000000817 · Cited by 25
“On the other hand, EPAS1 activation increases lipid- and iron-regulator gene expression in tumours, making these tumours more susceptible to ferroptosis and increasing ROS levels via irreversible cysteine oxidation (Singhal et al., 2021).”
BackgroundZhao, X.-N., Liu, S., Wang, Z., Zhang, S., & You, L.-L. (2023) · European journal of medical research · doi:10.1186/s40001-023-01179-3 · Cited by 27
Ferroptosis is an effective strategy for cancer therapy
Khan, A., Huo, Y., Guo, Y., Shi, J., & Hou, Y. (2024) · Medical Oncology · doi:10.1007/s12032-024-02317-5 · Cited by 24
“Furthermore, HIF-2α activation causes ferroptosis through enhancing lipid per-oxidation of PUFAs by irreversible cysteine oxidation [83].”
Xi, C., Pang, J., Xue, W., Cui, Y., Jiang, N., Zhi, W., Shi, H., Horuzsko, A., Pace, B. S., & Zhu, X. (2025) · Communications Biology · doi:10.1038/s42003-024-07424-7 · Cited by 26
Ferroptosis and bone health: bridging the gap between mechanisms and therapy
Xiao, R., Han, Z., Peng, J., Li, P., Gong, M., Cai, Y., Pang, L., Ye, X., & Jin, S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1634516 · Cited by 24
“GPX4 expression in chondrocytes increase their susceptibility to ferroptosis (Figure 4) (80, 161).”
Targeting ferroptosis in cancer: from mechanistic insights to therapeutic approaches
Wang, J., Guo, D., Jiang, S., Wu, W., & Gao, X. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00416-5 · Cited by 27
“Hypoxia-inducible factor-2α (HIF-2α) activation increased the cellular iron level and potentiated oxidative stress-related death in colorectal cancer [19].”
Zhang, L., Li, D., Chang, C., & Sun, Y. (2022) · International Journal of Chronic Obstructive Pulmonary Disease · doi:10.2147/copd.s377226 · Cited by 22
“Studies demonstrated that activation of HIF2α upregulated lipid and iron regulatory genes in murine colorectal cancer cells and colon tumors, and put cells into a ferroptosis-sensitive state and promoted cell death.(36) However, whether HIF mediates ferroptosis in skeletal muscle cells has not been reported.”
BackgroundHeme Oxygenase-1 and Its Role in Colorectal Cancer
Fahrer, J., Wittmann, S., Wolf, A., & Kostka, T. (2023) · Antioxidants · doi:10.3390/antiox12111989 · Cited by 27
“To sum up, HO-1 can prevent cells and tissue from damage, which could lead to tumor formation, while in established tumors and tumor cell lines the well-directed inhibition of HO-1 may increase apoptosis and reduce tumor size.”
BackgroundModulating Nrf2 to control lipid peroxidation and ferroptosis: implications for cancer management
Tunc, R., Ateş, İ., Yılmaz, B., Medoro, A., Davinelli, S., Süzen, S., & Saso, L. (2025) · Frontiers in Oncology · doi:10.3389/fonc.2025.1701249 · Cited by 21
Accumulation of Intracellular Ferrous Iron in Inflammatory-Activated Macrophages
Ma, H., Shu, Q., Li, D., Wang, T., Li, L., Song, X., Lou, K., & Xu, H. (2022) · Biological Trace Element Research · doi:10.1007/s12011-022-03362-9 · Cited by 24
“These signaling molecules were deeply involved in various metabolic processes, including Fe metabolism [33].”
BackgroundSESN2 prevents the slow-to-fast myofiber shift in denervated atrophy via AMPK/PGC-1α pathway
Yang, X., Xue, P., Liu, Z., Li, W., Li, C., & Chen, Z. (2022) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-022-00367-z · Cited by 24
“HIF-2α, as a member of the the Per–ARNT–Sim–bHLH family of transcription factors that regulate the cellular response to hypoxic conditions [26, 27], was also detected in the present study.”
BackgroundFerroptosis, a subtle talk between immune system and cancer cells: To be or not to be?
Zhou, Q., Tao, C., Yuan, J., Pan, F., & Wang, R. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115251 · Cited by 21
Lee, S.-A., Cho, G.-J., Kim, D., & Kim, D. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1335636 · Cited by 23
Insights on Ferroptosis and Colorectal Cancer: Progress and Updates
Hu, B.-L., Yin, Y., Li, S., & Guo, X. (2022) · Molecules · doi:10.3390/molecules28010243 · Cited by 20
“Inhibiting or knocking down HIF-2α decreases ROS generation and resistance to oxidative cell death in vitro and in vivo [46].”
BackgroundLactate metabolic checkpoint in immuno-oncology: mechanisms and therapeutic implications
Wang, Z., Gu, Z., Mo, W., & Zhang, H. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.218038 · Cited by 19
Guo, F., Zong, S., Zhang, X., Ren, Z., Shao, H., Li, J., Wang, X., Li, Y., Wang, X., & Chen, K. (2026) · Molecular Cancer · doi:10.1186/s12943-025-02544-y · Cited by 20
“…regulatory genes, producing a ferroptosis-susceptible state that couples iron load to oxidative death; loss of HIF-2α conversely diminishes ROS and protects from oxidative cell death, positioning hypoxic signaling as a context setter for vulnerability at iron-rich sites like the liver [129].”
Role of ferroptosis in colorectal cancer
Song, Y., Yan, X., Wang, Y., Wang, Z., Mao, X., Ye, L., & Li, S.-W. (2023) · World Journal of Gastrointestinal Oncology · doi:10.4251/wjgo.v15.i2.225 · Cited by 21
Huang, F., Huang, Z., Wei, Q., Liu, G., & Pu, J. (2023) · Experimental Cell Research · doi:10.1016/j.yexcr.2023.113697 · Cited by 19
Wang, Y., Ding, H., Zheng, Y., Wei, X., Yang, X., Wei, H., Tian, Y., Sun, X., Wei, W., Ma, J., et al. (2024) · Inflammation Research · doi:10.1007/s00011-023-01842-9 · Cited by 19
“In contrast, HIF-2α, equally important in hypoxia, activation potentiated ferroptosis through increasing the expression of PLIN2 and HILPDA, which both elevated lipid accumulation and oxidative stress [43].”
Zhou, Y., Wei, X., Ji, C., Ren, X., Su, W. C., Wang, Y., Zhou, J., Zhao, Z., Zhou, P., Zhao, K., et al. (2023) · iScience · doi:10.1016/j.isci.2023.108148 · Cited by 18
“HIF-2 a -induced sensitivity to ferroptosis underscores a prominent oncogene-induced vulnerability in ccRCC. 7,8 O-linked-N-acetylglucosamine (O-GlcNAc) modification is dynamic, reversible, posttranslational, and ubiquitous on protein serine/thre-onineresidues.”
BackgroundFerroptosis: Frenemy of Radiotherapy
Kerkhove, L., Geirnaert, F., Dufait, I., & Ridder, M. D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073641 · Cited by 19
Rashid, M. M., Corbin, B. A., Jella, P. K., Ortiz, C. J., Samee, M. A. H., Pautler, R. G., & Allen, M. J. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c10373 · Cited by 19
Advancing the frontiers of colorectal cancer treatment: harnessing ferroptosis regulation
Liu, S., Yue, M., Lu, Y., Wang, Y., Luo, S., Liu, X., & Jiang, J. (2023) · APOPTOSIS · doi:10.1007/s10495-023-01891-9 · Cited by 19
“Moreover, the activated HIF-2ɑ can boost irreversible oxidation cysteine to increase ROS level, thereby promoting CRC ferroptosis [67].”
InfluentialLei, B., Wu, H., You, G., Wan, X., Chen, S., Chen, L., Wu, J., & Zheng, N. (2023) · Biotechnology and Genetic Engineering Reviews · doi:10.1080/02648725.2023.2210449 · Cited by 16
“Many studies indicate that Hypoxic inducible factor 2α (HIF-2α) mediates hypoxia response, and continues to be highly expressed in hypoxia environment (J. Chen et al., 2019; Singhal et al., 2021).”
Herbal Medicine for Colorectal Cancer Treatment: Molecular Mechanisms and Clinical Applications
Su, Z., Li, Y., Zhou, Z., Feng, B. C., Chen, H., & Zheng, G. (2025) · Cell Proliferation · doi:10.1111/cpr.70065 · Cited by 16
“This process leads to several phenomena, including increased lipid peroxidation, failure of anti-oxidant defences, elevated ROS, mitochondrial atrophy and cell membrane rupture [109–111].”
Hypoxia induced lipid droplet accumulation promotes resistance to ferroptosis in prostate cancer
Chauhan, S. S., Vizzerra, A. D., Liou, H., Flores, C. E., Snider, A. J., Snider, J. M., & Warfel, N. A. (2025) · Oncotarget · doi:10.18632/oncotarget.28750 · Cited by 16
“Subsequent reports showed strong evidence that ferroptosis induction is HIF-2α dependent on colorectal cancer [38] clear-cell carcinomas [39].”
Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells
Mooli, R. G. R., Mukhi, D., Pasupulati, A. K., Evers, S. S., SIPULA, I. J., Jurczak, M. J., Seeley, R. J., Shah, Y. M., & Ramakrishnan, S. K. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.12.004 · Cited by 16
Self-citationWang, J., Tian, Q., Liu, Y., Cai, C., Fu, S., Li, J., Guan, Y., Liao, X., Su, D., Sun, T., et al. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02414-7 · Cited by 18
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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