HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron

Singhal, Rashi; Mitta, Sreedhar R.; Das, Nupur K.; Kerk, Samuel A.; Sajjakulnukit, Peter; Solanki, Sumeet; Andren, Anthony; Kumar, Roshan; Olive, Kenneth P.; Banerjee, Ruma; Lyssiotis, Costas A.; Shah, Yatrik M.

doi:10.1172/jci143691

Cited by 215Ferroptosis and cancer prognosisCancer, Hypoxia, and MetabolismCell death mechanisms and regulation

HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron

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Singhal, Rashi, Mitta, Sreedhar R., Das, Nupur K., Kerk, Samuel A., Sajjakulnukit, Peter, Solanki, Sumeet, Andren, Anthony, Kumar, Roshan +4 more·2021·Journal of Clinical Investigation

DOI 10.1172/jci143691PMC PMC8203462

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Abstract

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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HIF-2α inhibition might offer effective treatment for advanced ccRCC.
“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]
The Introduction (page unavailable) says the HIF-2α inhibitor PT2385 was in phase 2 trials for advanced ccRCC, and the Discussion (page unavailable) says inhibitors in clinical trials had shown promise, while noting acquired resistance. This supports the qualified possibility of effective treatment, but the paper does not report the cited sentence’s claim of significant belzutifan efficacy in heavily pretreated metastatic RCC. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Belzutifan has shown significant efficacy in heavily pretreated metastatic RCC.
“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]
The Introduction describes PT2385, a different HIF-2α inhibitor, as being in phase 2 trials for advanced ccRCC, and the Discussion says HIF-2α inhibitors in clinical trials have shown promise. Neither passage reports belzutifan’s efficacy or results in heavily pretreated metastatic RCC. (LLM, conf=0.83)
Experimental — accuracy not yet measured

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Hypoxia inducible factor-2α increases sensitivity of colon cancer cells towards oxidative cell deathPreprint
Singhal, R., Mitta, S. R., Olive, K. P., Lyssiotis, C. A., & Shah, Y. M. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/823997 · Cited by 4 · see citing works
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Targeting HIF-2α in colorectal cancer reveals a cholesterol biosynthesis–dependent ferroptotic vulnerability
Dalal, P. J., Singhal, R., Hu, B., Stark, D. C., Rossiter, N. J., Jain, C., Sajjakulnukit, P., Lyssiotis, C., & Shah, Y. M. (2026) · bioRxiv · doi:10.1186/s40170-026-00421-w · Cited by 2 · see citing works
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Additional file 1 of Targeting HIF-2α in colorectal cancer reveals a cholesterol biosynthesis–dependent ferroptotic vulnerability
Dalal, P., Singhal, R., Hu, B., Stark, D. C., Rossiter, N. J., Jain, C., Sajjakulnukit, P., Lyssiotis, C. A., & Shah, Y. M. (2026) · Figshare · doi:10.6084/m9.figshare.31810126
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Additional file 2 of Targeting HIF-2α in colorectal cancer reveals a cholesterol biosynthesis–dependent ferroptotic vulnerability
Dalal, P., Singhal, R., Hu, B., Stark, D. C., Rossiter, N. J., Jain, C., Sajjakulnukit, P., Lyssiotis, C. A., & Shah, Y. M. (2026) · Figshare · doi:10.6084/m9.figshare.31810129
Self-citation

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: Singhal, Rashi
Das, Nupur K.
Kerk, Samuel A.
Sajjakulnukit, Peter
Solanki, Sumeet
Andren, Anthony
Kumar, Roshan
Olive, Kenneth P.
Banerjee, Ruma
Lyssiotis, Costas A.
Shah, Yatrik M.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2021-06-15
Volume: 131
Issue: 12
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci143691
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: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › 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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HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron

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