HIF1α/PRDX1 axis drives pulmonary vascular remodeling through DRP1 DeSUMOylation and mitochondrial fragmentation

Pulmonary hypertension (PH) is a lethal vascular disorder characterized by hypoxia-driven vascular remodeling, yet the molecular mechanisms underlying endothelial dysfunction remain poorly understood. Here, we identify peroxiredoxin-1 (PRDX1) as a critical mediator of PH pathogenesis through redox-independent regulation of mitochondrial dynamics. Hypoxia upregulated PRDX1 expression in human pulmonary artery endothelial cells (HPAECs) via HIF1α-dependent transcriptional activation, as demonstrated by chromatin immunoprecipitation and promoter-luciferase assays. PRDX1 silencing attenuated hypoxia-induced HPAEC proliferation and apoptosis resistance, while its overexpression mimicked hypoxic effects independently of its antioxidant activity. Mechanistically, PRDX1 directly interacted with Dynamin-related protein 1 (DRP1) and facilitated sentrin-specific protease 3 (SENP3) binding, suppressing DRP1 SUMO2/3 conjugation to promote mitochondrial fission. In vivo, endothelial-specific PRDX1 knockdown in a hypoxia/SU5416(SuHx)-induced PH rat model significantly reduced right ventricular systolic pressure, vascular wall thickening, and endothelial hyperproliferation, while improving exercise tolerance. These findings reveal a novel HIF1α-PRDX1-DRP1 axis driving mitochondrial fragmentation and vascular remodeling in PH, positioning PRDX1 as a promising therapeutic target for halting disease progression.