Targeting Ferroptosis Alleviates Pulmonary Arterial Hypertension, Insights from Transcriptomic and Experimental Analyses

Abstract Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling driven by endothelial cell injury. This study investigates the role of ferroptosis in PAH development and its underlying molecular mechanisms. Ferroptosis‐related gene expression is analyzed using transcriptomic and single‐cell RNA sequencing data. A PAH mouse model is induced by combined hypoxia and Semaxanib (SU5416) treatment. The impact of ferroptosis on pulmonary vascular remodeling is evaluated by measuring right ventricular systolic pressure (RVSP), the Fulton index, vascular wall thickness, and histological changes in pulmonary arteries. Transcriptomic analysis reveals downregulation of SLC7A11 and upregulation of ACSL1 and ACSL4 in PAH patients. Endothelial cells are identified as key mediators of ferroptosis, and inhibiting ferroptosis alleviates endothelial damage and vascular remodeling. Additionally, HIF1α signaling plays a crucial role in ferroptosis induction in PAH. These findings highlight ferroptosis as a critical mechanism of endothelial injury and a key contributor to PAH pathogenesis. Targeting ferroptosis offers promising new strategies for early intervention and targeted therapy in PAH.