{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T10:04:09Z","timestamp":1775556249124,"version":"3.50.1"},"reference-count":52,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T00:00:00Z","timestamp":1747785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Laboratory of High Altitude Medicine (Ministry of Education)"},{"name":"Key Laboratory of Application"},{"name":"Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Iron deficiency is highly prevalent in patients with idiopathic pulmonary hypertension; nevertheless, its role and clinical significance in hypoxic pulmonary hypertension (HPH) remain elusive. Therefore, this study aims to clarify the role and molecular mechanisms of iron in HPH. By means of a retrospective analysis of clinical data from HPH patients and examinations of HPH animal models, we discovered that both HPH patients and animal models exhibit significant iron deficiency, characterized by reduced hepatic iron storage and elevated hepcidin expression. To further explore iron\u2019s role in HPH, we modulated iron metabolism through pharmacological and dietary interventions in chronic hypoxic animal models. The results showed that iron deficiency exacerbated chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy, while iron supplementation alleviated these conditions. Further investigations revealed that iron regulates HIF2\u03b1 expression in pulmonary arterial endothelial cells (PAECs) under chronic hypoxia. Therefore, through in vivo and in vitro experiments, we demonstrated that HIF2\u03b1 inhibition attenuates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Mechanistically, chronic hypoxia-mediated iron deficiency enhances HIF2\u03b1 activation, subsequently suppressing iron\/sulfur cluster assembly enzyme (ISCU) expression. This leads to decreased mitochondrial complexes I and III activity, increased reactive oxygen species (ROS) production, and inhibited oxidative phosphorylation. Consequently, metabolic reprogramming in PAECs results in a proliferation\/apoptosis imbalance, ultimately exacerbating hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Collectively, our findings demonstrate that iron supplementation mitigates HPH progression by modulating HIF2\u03b1-mediated metabolic reprogramming in PAECs, revealing multiple therapeutic targets for HPH.<\/jats:p>","DOI":"10.3390\/biom15050742","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T04:05:17Z","timestamp":1747800317000},"page":"742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Iron Replacement Attenuates Hypoxic Pulmonary Hypertension by Remodeling Energy Metabolism via Regulating the HIF2\u03b1\/Mitochondrial Complex I, III\/ROS Axis"],"prefix":"10.3390","volume":"15","author":[{"given":"Yumei","family":"Geng","sequence":"first","affiliation":[{"name":"Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China"},{"name":"Key Laboratory of High Altitude Medicine (Ministry of Education), Qinghai University, Xining 810001, China"},{"name":"Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Qinghai University, Xining 810001, China"},{"name":"Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining 810001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huijie","family":"Wang","sequence":"additional","affiliation":[{"name":"Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China"},{"name":"Key Laboratory of High Altitude Medicine (Ministry of Education), Qinghai University, Xining 810001, China"},{"name":"Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Qinghai University, Xining 810001, China"},{"name":"Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining 810001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4213-3605","authenticated-orcid":false,"given":"Zhenzhong","family":"Bai","sequence":"additional","affiliation":[{"name":"Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China"},{"name":"Key Laboratory of High Altitude Medicine (Ministry of Education), Qinghai University, Xining 810001, China"},{"name":"Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Qinghai University, Xining 810001, China"},{"name":"Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining 810001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rili","family":"Ge","sequence":"additional","affiliation":[{"name":"Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China"},{"name":"Key Laboratory of High Altitude Medicine (Ministry of Education), Qinghai University, Xining 810001, China"},{"name":"Key Laboratory of Application and Foundation for High Altitude Medicine Research in Qinghai Province (Qinghai-Utah Joint Research Key Lab for High Altitude Medicine), Qinghai University, Xining 810001, China"},{"name":"Laboratory for High Altitude Medicine of Qinghai Province, Qinghai University, Xining 810001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41572-024-00493-2","article-title":"Pulmonary hypertension","volume":"10","author":"Mocumbi","year":"2024","journal-title":"Nat. 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