The natural flavonoid pinocembrin shows antithrombotic activity and suppresses septic thrombosis

Sepsis, an extreme host response to systemic infection, remains one of the leading causes of mortality worldwide. Platelets, which are integral to both thrombosis and inflammation, play a crucial role in the pathophysiology of sepsis. Excessive platelet activation and aggregation significantly increase the risk of thrombosis, thereby elevating mortality in septic patients. However, the etiology and treatment of this condition have not been comprehensively studied. This study identifies pinocembrin, a natural flavonoid compound derived from propolis, as a potential therapeutic agent for mitigating platelet activation and treating sepsis. In vivo, pinocembrin effectively inhibited FeCl₃-induced carotid arterial occlusive thrombus formation and collagen/epinephrine-induced pulmonary thromboembolism in mouse models. In vitro, pinocembrin treatment suppressed multiple facets of platelet activation, including aggregation, secretion, and αIIbβ3-mediated signaling events. Mechanistically, pinocembrin repressed platelet functions by inhibiting Src/Syk/PLCγ2/MAPK signaling pathway. Using cecal ligation and puncture (CLP) mouse model to simulate human sepsis, pinocembrin reduced inflammatory cytokine release and septic thrombosis, thereby improving the survival rate of septic mice. Lipopolysaccharide (LPS)-induced model further substantiated these results. Overall, the inhibition of platelet activity by pinocembrin demonstrates significant therapeutic potential for managing life-threatening septic thrombosis.