{"doi":"10.1002/hem3.70271","title":"VHL, transferrin, and erythropoietin in the regulation of hepcidin","abstract":"Hepcidin, the master regulator of iron metabolism, is a hepatic peptide hormone that inhibits the absorption of iron by enterocytes and the release of iron from macrophages through interaction with ferroportin in the cellular membrane.1 Hepcidin binds to ferroportin, occluding it and causing it to move to the interior of cells, thereby preventing the release of cellular iron to plasma, and also causing a conformational change that leads to ferroportin ubiquitination and lysosomal degradation.2 Hepcidin is upregulated in response to (1) higher intracellular iron stores and plasma iron concentrations as reflected by serum ferritin and elevated circulating transferrin-bound iron3 via a bone morphogenetic protein receptor complex4 and (2) inflammation through interleukin-6 and a JAK-STAT pathway.5 Hepcidin is downregulated by increased erythropoiesis via erythroferrone secreted by erythroblasts, which suppresses bone morphogenetic protein receptor complex signaling.6 Hypoxia downregulates hepcidin mostly indirectly, via erythropoietin and erythroferrone.7 Upregulation of hypoxia sensing as seen in Chuvash erythrocytosis also leads to increased erythropoietin and erythroferrone and decreased hepcidin.8-10 The relationship of hepcidin to transferrin concentration in a model that includes ferritin, erythropoietin, and upregulated hypoxia sensing has not previously been reported. Hypoxia-inducible factors (HIFs) are dimers of a common HIF-β subunit and one of several HIF-α subunits that are regulated posttranslationally; HIF-1 and HIF-2 are best studied.11 Prolyl hydroxylases (PHDs, Fe-dependent enzymes) are the principal negative regulators of HIF-α subunits. In the presence of O2 and α-ketoglutarate, HIF-1α and HIF-2α subunits are hydroxylated by PHDs, facilitating binding to von Hippel–Lindau (VHL) protein, which leads to their ubiquitination and rapid proteosomal degradation.12, 13 In hypoxia and iron deficiency, degradation of HIF-α decreases, leading to increased HIF-1 and HIF-2 heterodimers that augment transcription of hypoxia-inducible genes.11 Homozygous germline loss-of-function VHLR200W causes congenital Chuvash erythrocytosis with thrombosis as the major cause of morbidity and mortality. VHLR200W homozygosity leads to decreased ubiquitination of HIF-1α and HIF-2α,8 which is necessary for their degradation. In turn, HIFs upregulate several genes that influence oxygen homeostasis, erythropoiesis, and iron metabolism.8, 14, 15 Erythropoietin, upregulated by hypoxia and iron deficiency via HIF-2,16 is increased in VHLR200W homozygotes even in the absence of hypoxia or iron deficiency,8, 17 and erythroferrone expression is increased in VHLR200W homozygote erythroid progenitors.10 Transferrin, upregulated at least in part by HIF-1 during hypoxia and iron deficiency,14 is also increased in VHLR200W homozygotes even in the absence of hypoxia or iron deficiency.18 We reported that in Chuvash erythrocytosis, hepcidin and ferritin levels are low, and erythropoietin levels are high.9 In multivariable analysis, hepcidin was decreased by VHLR200W homozygosity and correlated positively with ferritin, but did not correlate with erythropoietin after adjustment for VHLR200W homozygosity. However, we did not examine the HIF upregulated gene, transferrin, or perform a pathway analysis. We have now reexamined the relationship of VHLR200W homozygosity with hepcidin related to both HIF-2-mediated enhancement of erythropoietin and HIF-mediated augmentation of transferrin, which is at least in part mediated by HIF-1. The research was Institutional Review Board (IRB) approved. Participants lived in the Chuvash Autonomous Republic of the Russian Federation, located about 650 km southeast of Moscow along the Volga River. We studied 111 VHLR200W homozygotes and 29 controls without mutated VHL. We previously reported hepcidin, ferritin, and erythropoietin levels but not transferrin concentrations in the controls and 90 of the VHLR200W homozygotes in t","journal":"HemaSphere","year":2025,"id":584753,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.955,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":301181,"name":"Josef T. Prchal","orcid":"0000-0002-8019-2940","position":1,"is_corresponding":false},{"id":431407,"name":"Seyed Mehdi Nouraie","orcid":null,"position":2,"is_corresponding":false},{"id":269842,"name":"Binal N. Shah","orcid":"0000-0001-5169-7301","position":3,"is_corresponding":false},{"id":351694,"name":"Xu Zhang","orcid":"0000-0002-7732-1385","position":4,"is_corresponding":false},{"id":438542,"name":"Adelina Sergueeva","orcid":null,"position":5,"is_corresponding":false},{"id":438541,"name":"Galina Miasnikova","orcid":null,"position":6,"is_corresponding":false},{"id":374947,"name":"Tomas Ganz","orcid":"0000-0002-2830-5469","position":7,"is_corresponding":false},{"id":269831,"name":"Victor R. Gordeuk","orcid":"0000-0003-4725-7295","position":8,"is_corresponding":false},{"id":1497871,"name":"И. В. Сергеев","orcid":"0000-0002-0233-0519","position":0,"is_corresponding":true}],"reference_count":20,"raw_metadata":null,"created_at":"2026-07-19T02:59:16.166424Z","pmid":"41362631","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":[]}