Hederagenin Ameliorates Inferior Vena Cava Thrombosis via Modulating the MDM2-p53 Axis to Concurrently Suppress NF-κB-Mediated Endothelial Inflammation, Oxidative Stress, and Platelet Activation

Aim: The aim of this study was to investigate the antioxidant and anti-inflammatory potential of hederagenin (HD), a natural bioactive compound from the Sparganii Rhizoma–Curcumae Rhizoma herb pair, in deep vein thrombosis (DVT) and to elucidate its mechanism via the MDM2–p53 axis. Methods: A rat DVT model induced by inferior vena cava stenosis and an oxygen–glucose deprivation (OGD)-stimulated EA.hy926 endothelial cell model were established. Rats received HD (12.5, 25, 50 mg/kg) or heparin. Thrombus weight, coagulation, histopathology, immunofluorescence, immunohistochemistry, and Western blot were assessed. Inflammatory cytokines (TNF-α, IL-1β, CRP) and oxidative stress markers (SOD, MDA) were measured. Platelet aggregation was induced by ADP, arachidonic acid, and thrombin. Network pharmacology, molecular docking, and molecular dynamics simulations were performed. Results: HD dose-dependently reduced thrombus weight, improved coagulation, and downregulated tissue factor and von Willebrand factor. HD decreased TNF-α, IL-1β, CRP, and MDA levels and restored SOD activity, demonstrating antioxidant and anti-inflammatory effects. Network pharmacology identified MDM2 as a core target. Molecular docking showed favorable HD–MDM2 binding (−8.2 kcal/mol), and 100 ns molecular dynamics confirmed complex stability. HD downregulated MDM2, upregulated p53/p-p53, and suppressed NF-κB p65 phosphorylation and acetylation in IVC tissues and OGD-stimulated cells. HD also inhibited platelet aggregation, reduced vWF release, and downregulated CD41/CD61. Conclusions: HD, a natural bioactive compound, attenuates DVT through antioxidant and anti-inflammatory mechanisms by modulating the MDM2–p53 axis, concurrently suppressing endothelial inflammation, oxidative stress, and platelet activation. It is a promising dual-acting candidate for DVT therapy.