Pterostilbene attenuates lung ischemia-reperfusion injury: integrative insights from network pharmacology, molecular dynamics, and experimental validation

Background: Lung ischemia-reperfusion injury (LIRI) is a principal cause of primary graft dysfunction (PGD) following lung transplantation, severely compromising recipient survival. However, effective therapies remain unavailable due to its complex pathophysiology. Pterostilbene (PTE) is a natural stilbene compound known for its well-documented anti-inflammatory, antioxidant, and antitumor properties. However, its effects and underlying mechanisms in LIRI remain unclear. Methods: Potential targets of PTE and LIRI were retrieved from multiple public databases, followed by network analysis and functional enrichment to identify core targets and pathways. Molecular docking and dynamics simulations were conducted to assess the binding affinity and stability between PTE and its core targets. Finally, a rat left hilar clamping model and an OGD/R model in BEAS-2B cells were employed to experimentally validate the protective effects and molecular mechanisms of PTE. Results: . Notably, LY294002 (a PI3K inhibitor) and Anisomycin (a JNK activator) partially reversed the anti-apoptotic and anti-inflammatory effects of PTE, respectively. Conclusion: This study provides the first integrated evidence combining network pharmacology and experimental validation that PTE protects against LIRI by modulating the PI3K/AKT and JNK/c-Jun signaling pathways, offering novel pharmacological insights into its translational potential in LIRI.