Key result
Iron supplementation attenuates hypoxic pulmonary hypertension and RV hypertrophy via HIF2α-mediated endothelial metabolic reprogramming.
Why the study?
Iron deficiency is prevalent in idiopathic pulmonary hypertension, but its role and clinical significance in hypoxic pulmonary hypertension remain elusive.
Does iron supplementation alleviate hypoxic pulmonary hypertension in chronic hypoxia models?
Does iron supplementation alleviate hypoxic pulmonary hypertension in chronic hypoxia models?
Iron supplementation represents a potential therapeutic strategy for hypoxic pulmonary hypertension by targeting HIF2α-mediated metabolic reprogramming and mitochondrial ROS production.
Hypothesis-generating for iron repletion in hypoxic PH; prospective trials required before any clinical adoption.
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's 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 HIF2α expression in pulmonary arterial endothelial cells (PAECs) under chronic hypoxia. Therefore, through in vivo and in vitro experiments, we demonstrated that HIF2α inhibition attenuates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy. Mechanistically, chronic hypoxia-mediated iron deficiency enhances HIF2α 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 HIF2α-mediated metabolic reprogramming in PAECs, revealing multiple therapeutic targets for HPH.
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Geng et al. (2025) studied Hypoxic pulmonary hypertension (HPH) (n=169). Iron supplementation vs. Vehicle or standard chow under hypoxic conditions was evaluated on Pulmonary arterial pressure and right ventricular hypertrophy. Iron supplementation mitigates hypoxic pulmonary hypertension progression and right ventricular hypertrophy by modulating HIF2α-mediated metabolic reprogramming in pulmonary arterial endothelial cells.
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