Potential of Sivelestat for Pulmonary Arterial Hypertension Treatment: Network Pharmacology-Based Target Identification and Mechanistic Exploration.

BACKGROUND: Sivelestat is a specific neutrophil elastase inhibitor that is currently approved for the treatment of acute lung injury and acute respiratory distress syndrome. Given sivelestat's established anti-inflammatory and antioxidant properties, its efficacy in treating pulmonary arterial hypertension (PAH) remains uncertain. This study aims to investigate the potential of sivelestat as a treatment for PAH. METHODS: Sivelestat's effects on PAH were evaluated using hypoxia-induced rat models (10% O(2), 4 weeks) and pulmonary arterial endothelial/smooth muscle cells (1% O(2)). Rats received sivelestat (20-100 mg/kg) for 2 weeks, with hemodynamic (RVSP) and vascular remodeling (%WT) assessments. In vitro, sivelestat (50-200 μM) suppressed hypoxia-driven proliferation (CCK-8, EdU), migration (Transwell), and angiogenesis. Molecular validation via qPCR/Western blot confirmed reduced expression of key targets (IGF1R, JAK1, JAK2, PDGFRB). RESULTS: Through predictive analysis, we identified 595 potential genes associated with sivelestat in the treatment of PAH. Notably, ERBB2, IGF1R, JAK1, JAK2, PDGFRB, and PTPN11 emerged as key hub genes. In vivo experiments demonstrated that administration of sivelestat at a dose of 100 mg/kg significantly reduced PAH and improved pulmonary vascular remodeling. In vitro experiments indicated that sivelestat effectively decreased the proliferation and migration of PAECs and PASMCs induced by hypoxia. CONCLUSION: Sivelestat has the potential to treat PAH through various targets and pathways. We have initially elucidated the molecular mechanism by which sivelestat acts in the treatment of PAH and have conducted preliminary validation through molecular docking studies and experimental approaches.