{"doi":"10.1002/advs.202307022","title":"Activation of Intestinal HIF2α Ameliorates Iron‐Refractory Anemia","abstract":"In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.","journal":"Advanced Science","year":2024,"id":436058,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9564,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1244153,"name":"Yunxing Su","orcid":"0000-0002-7906-3885","position":1,"is_corresponding":false},{"id":935913,"name":"Sisi Yang","orcid":"0009-0008-2696-9107","position":2,"is_corresponding":false},{"id":705203,"name":"Yutong Liu","orcid":"0009-0005-1760-8308","position":3,"is_corresponding":false},{"id":1244154,"name":"Zhiting Lin","orcid":"0000-0002-3314-1606","position":4,"is_corresponding":false},{"id":619219,"name":"Nupur K. Das","orcid":"0000-0002-5652-1134","position":5,"is_corresponding":false},{"id":1196671,"name":"Qian Wu","orcid":"0000-0003-3934-0128","position":6,"is_corresponding":false},{"id":1221937,"name":"Jiahui Zhou","orcid":"0009-0008-3354-369X","position":7,"is_corresponding":false},{"id":1244155,"name":"Shumin Sun","orcid":"0000-0002-6498-9685","position":8,"is_corresponding":false},{"id":242007,"name":"Xiaopeng Li","orcid":"0000-0001-9655-9551","position":9,"is_corresponding":false},{"id":1244156,"name":"Wuyang Yue","orcid":"0000-0002-5622-8165","position":10,"is_corresponding":false},{"id":432386,"name":"Yatrik M. Shah","orcid":"0000-0002-2487-4816","position":11,"is_corresponding":false},{"id":371165,"name":"Junxia Min","orcid":"0000-0001-8099-6327","position":12,"is_corresponding":false},{"id":838868,"name":"Fudi Wang","orcid":"0000-0001-8730-0003","position":13,"is_corresponding":false},{"id":1244152,"name":"Yingying Yu","orcid":"0000-0002-9857-2407","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T02:00:12.706156Z","pmid":"38243847","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":[]}