{"doi":"10.1172/jci143691","title":"HIF-2α activation potentiates oxidative cell death in colorectal cancers by increasing cellular iron","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.","journal":"Journal of Clinical Investigation","year":2021,"id":146523,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":214,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":624435,"name":"Sreedhar R. Mitta","orcid":null,"position":1,"is_corresponding":false},{"id":619219,"name":"Nupur K. Das","orcid":"0000-0002-5652-1134","position":2,"is_corresponding":false},{"id":289064,"name":"Samuel A. Kerk","orcid":"0000-0001-9786-2245","position":3,"is_corresponding":false},{"id":106339,"name":"Peter Sajjakulnukit","orcid":"0000-0002-8556-7481","position":4,"is_corresponding":false},{"id":619220,"name":"Sumeet Solanki","orcid":"0000-0002-2773-3082","position":5,"is_corresponding":false},{"id":566027,"name":"Anthony Andren","orcid":"0000-0002-0385-527X","position":6,"is_corresponding":false},{"id":31917,"name":"Roshan Kumar","orcid":"0000-0002-5372-8682","position":7,"is_corresponding":false},{"id":106352,"name":"Kenneth P. Olive","orcid":"0000-0002-3392-8994","position":8,"is_corresponding":false},{"id":265994,"name":"Ruma Banerjee","orcid":"0000-0001-8332-3275","position":9,"is_corresponding":false},{"id":106351,"name":"Costas A. Lyssiotis","orcid":"0000-0001-9309-6141","position":10,"is_corresponding":false},{"id":432386,"name":"Yatrik M. Shah","orcid":"0000-0002-2487-4816","position":11,"is_corresponding":false},{"id":619218,"name":"Rashi Singhal","orcid":"0000-0003-2685-5667","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-18T23:42:24.567796Z","pmid":"33914705","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}