P2Y12 receptor-independent antiplatelet mechanism of cryptotanshinone: network pharmacology and experimental validation of multi-target signaling pathways

Ethnopharmacological relevance: Cryptotanshinone serves as the principal bioactive constituent of Salvia miltiorrhiza Bunge, possesses a wide range of pharmacological activities. Salvia miltiorrhiza Bunge, a long-standing therapeutic agent in traditional Chinese medicine (TCM) practice, is renowned for its efficacy in enhancing blood circulation and alleviating blood stasis and infarction, thereby treating cardiovascular and cerebrovascular diseases.

Aim of the study: Platelet activation, when excessive or aberrant, poses a significant risk, catalyzing the onset of various thrombotic disorders. Thus, this investigation is meticulously designed to assess the antiplatelet pharmacological activity of cryptotanshinone, delving into its mechanisms of action that operate independently of the P2Y12 receptor.

Materials and methods: We employed a combination of isolated human platelet functional analysis, network pharmacology, molecular docking, and animal experiments to explore the P2Y12 receptor-independent antiplatelet targets and the biological mechanisms by which cryptotanshinone improves thrombosis.

Results: Utilizing the ADP-hydrolyzing enzyme apyrase, we isolated the direct effects of cryptotanshinone on platelet function. The findings reveal that cryptotanshinone can effectively inhibit platelet activation in a manner that is independent of the P2Y12 receptor, all the while maintaining normal tail bleeding times in murine models and not exacerbating mesenteric thrombosis. These effects appear to be mediated through intricate signaling pathways, including PI3K-AKT, MAPK, and STAT3.

Conclusion: This study compellingly confirms the capacity of cryptotanshinone to suppress platelet function independently of the P2Y12 receptor, establishing a robust theoretical foundation for innovative strategies in thrombosis prevention.