Cyclomulberrin from Morus alba L. exerts antithrombotic effects by modulating platelet activation: an integrated...

Despite the documented bioactivity of Morus alba L., the antithrombotic mechanism of its constituent flavonoid cyclomulberrin is not fully understood. Here, we applied network pharmacology, molecular docking/dynamics, and in vitro assays to evaluate its antithrombotic properties. The compound was isolated from Sang-Bai-Pi (root bark of M. alba L). Network pharmacology identified 57 potential targets and seven hub targets (TNF, AKT1, SRC, PTGS2, MMP9, PPARG, CYCS) enriched in platelet activation, PI3K-Akt, cAMP, and TNF pathways. Molecular docking and 100-ns molecular dynamics simulations confirmed stable binding to all seven hubs. Selective inhibitor experiments (PP2, MK-2206) confirmed functional engagement of SRC and AKT1. Cyclomulberrin potently inhibited key platelet responses: aggregation, ATP release, αIIbβ3 activation, Ca²⁺ mobilization, and ROS generation, while elevating cAMP. Coagulation parameters were unaffected below 40 µM. Our results demonstrate that cyclomulberrin engages multiple targets via a multi-pathway mechanism, positioning it as a promising natural-source antithrombotic agent.