ArticleThe Journal of clinical investigation2021
HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 134 papers.
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Who cites it
134 citing papers in PubMed, 196 citations in OpenAlex.
- Rewiring redox defense: Nrf2-driven antioxidant signaling as a gateway to programmed cell death activation in colorectal cancer.Genes & diseases · 2027Review
- Ferroptosis and tumor microenvironment: orchestrating therapy resistance, immune evasion, and metastatic events.Medical oncology (Northwood, London, England) · 2026Review
- Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death.Cell metabolism · 2026Article
- HIFs: The central drivers of tumors and their role as molecular switches in targeted therapy?Acta pharmaceutica Sinica. B · 2026Review
- Fatty Acid Metabolism and Hypoxia in the Tumor Microenvironment: Metabolic Adaptation and Clinical Potential in Colorectal Cancer.Biomedicines · 2026Review
- The clinical landscape of HIF2α inhibitors in oncology.Nature reviews. Clinical oncology · 2026Review
- Lipid droplets as stress-buffering organelles in cancer cell homeostasis.Communications biology · 2026Review
- Iron Metabolism in the Colorectal Tumor Microenvironment: From Preneoplastic Lesions to Cancer Progression.International journal of molecular sciences · 2026Review
- IL-1β/EPAS1-Associated Ferroptotic Stress Impairs Skeletal Stem/Progenitor Cell Function in Inflammation-Associated Fracture Nonunion.Current issues in molecular biology · 2026Article
- Translating ferroptosis into oncology: challenges, opportunities and future directions.Nature reviews. Clinical oncology · 2026Review
- Labile iron pool dynamics do not drive ferroptosis in colorectal cancer cells.The Journal of biological chemistry · 2026Article
- Fibroblast-specificAmerican journal of physiology. Gastrointestinal and liver physiology · 2026Article
- Andrographis exerts antitumor effects and enhances 5‑FU efficacy via the alteration of ferroptosis‑related genes in esophageal squamous cell carcinoma.Oncology reports · 2026Article
- The Interaction Between Iron and Selenium Affects Ferroptosis in Colorectal Cancer.International journal of molecular sciences · 2026Review
- Decoding the spatiotemporal characteristics of ferroptosis: reshaping tumour therapeutic strategies.Experimental hematology & oncology · 2026Review
- Targeting dormant cancer cells: ferroptosis as a precision therapeutic strategy.Cellular & molecular biology letters · 2026Review
- Targeting ferroptosis in cancer: from mechanistic insights to therapeutic approaches.Molecular biomedicine · 2026Review
- Targeting HIF-2α in colorectal cancer reveals a cholesterol biosynthesis-dependent ferroptotic vulnerability.Cancer & metabolism · 2026Article
- Epithelial HO-1 regulates iron availability and promotes colonic tumorigenesis in a context-dependent manner.JCI insight · 2026Article
- Targeting HIF-2α in Colorectal Cancer Reveals a Cholesterol Biosynthesis-Dependent Ferroptotic Vulnerability.bioRxiv : the preprint server for biology · 2026Article
74 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.