Shengxian decoction ameliorates hypoxic pulmonary hypertension via the LOX-1/P47phox/SRC/NF-κB pathway: A multi-omics study

Background Hypoxic pulmonary hypertension (HPH) is a severe condition associated with vascular remodeling, right ventricular hypertrophy, and elevated pulmonary arterial pressure, particularly at high altitudes. Shengxian decoction (SXT), a classical Traditional Chinese Medicine (TCM) formula, has historically been used to treat pectoral qi deficiency syndromes related to cardiopulmonary dysfunction. However, its therapeutic mechanisms in HPH remain unclear. Methods A multi-omics approach integrating transcriptomics and metabolomics was employed to investigate the effects of SXT in an HPH animal model. Pulmonary artery smooth muscle cells (PASMCs) were exposed to hypoxic conditions in both in vivo and in vitro models. The therapeutic effects of SXT were evaluated using hemodynamic measurements, histopathological analysis, immunohistochemistry, RT-qPCR, Western blotting, flow cytometry, and EdU proliferation assays. Key signaling pathways were further validated using LOX-1 overexpression and knockdown models. Results SXT treatment significantly reduced mean pulmonary arterial pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in HPH rats. Multi-omics analyses identified the LOX-1/P47phox/SRC/NF-κB signaling pathway as a key regulatory target. In vitro experiments demonstrated that SXT inhibited PASMCs proliferation and promoted apoptosis by regulating the LOX-1/P47phox/SRC/NF-κB signaling pathways. These effects were further confirmed in gene silencing and gene overexpression experiments. Conclusions SXT exerts protective effects against HPH by inhibiting the LOX-1/P47phox/SRC/NF-κB signaling pathway, thereby attenuating hypoxia-induced vascular remodeling. These findings provide mechanistic insight into the therapeutic potential of SXT and supports its modernization and clinical application in the treatment of HPH based on TCM theory.