Thioredoxin‐Interacting Protein‐Regulated in Development and DNA Damage‐Response 1‐Driven Macrophage Senescence Promotes Hypoxia‐Induced Pulmonary Hypertension

Background Pulmonary hypertension (PH) is a life‐threatening vascular disorder characterized by pulmonary arterial remodeling and right ventricular failure, posing a significant clinical challenge. Although macrophage dysfunction is implicated in PH pathogenesis, its underlying molecular mechanisms remain elusive. Methods We employed multiomics database analysis, cross‐species validation, and functional studies in hypoxia‐induced PH models. Myeloid‐specific Txnip deletion was achieved via bone marrow transplantation in mice. Mechanistic insights were evaluated through protein‐binding assays, cellular senescence analyses in bone marrow‐derived macrophages, and co‐culture experiments with pulmonary artery smooth muscle cells. Results We identified that cellular senescence in pulmonary adventitial macrophages was involved in the pathogenesis of hypoxia‐induced PH. Integrated multiomics analysis revealed elevated TXNIP (thioredoxin‐interacting protein) expression in perivascular macrophages during hypoxia‐induced PH. Myeloid‐specific Txnip deletion attenuated hypoxia‐induced pulmonary vascular remodeling in mice. Mechanistically, TXNIP binds to and stabilizes the REDD1 (regulated in development and DNA damage‐response 1) protein, promoting hypoxia‐induced senescence in bone marrow‐derived macrophages. Conditioned medium from senescent macrophages subsequently enhanced the proliferation and migration of pulmonary artery smooth muscle cells. Conclusions The TXNIP‐REDD1 axis drives hypoxia‐induced macrophage senescence, which promotes pulmonary artery smooth muscle cell dysfunction and pulmonary vascular remodeling in hypoxia‐induced PH. Targeting the TXNIP‐REDD1 pathway may provide a novel therapeutic strategy for hypoxia‐induced PH.