Recently, the Hu Qinghua/Zhou Mengze team at our university published their latest research findings in the top international cardiovascular journal European Heart Journal: Targeting P2Y14R alleviates platelet-induced NET formation and venous thrombosis through the PKA/AKAP13/RhoA axis. The study first revealed that activation of the purinergic receptor P2Y14R regulates the release of neutrophil extracellular traps (NETs) through neutrophil-platelet interactions, thereby driving the core mechanism of inflammatory thrombosis. It also demonstrates that the established drug clopidogrel selectively inhibits P2Y14R, effectively reducing inferior vena cava thrombosis and pulmonary microthrombus formation in mice, offering a novel strategy for preventing and treating inflammatory thrombosis. Pharm.D. candidate Fang Yafei served as the first author of this paper. Corresponding authors include Professor Hu Qinghua and Associate Researcher Zhou Mengze from our university, alongside Professor Zhou Min from Gulou Hospital. China Pharmaceutical University is listed as the first corresponding institution.
Venous thromboembolism (VTE) ranks as the third leading cause of cardiovascular mortality after myocardial infarction and stroke, posing a severe threat to human health. Common risk factors include prolonged immobilization following major surgery, severe trauma, or fractures; physiological states such as pregnancy; and pharmacological conditions like estrogen replacement therapy. Additionally, patients with malignant tumors or chronic inflammatory diseases exhibit significantly elevated VTE risk. Existing antithrombotic drugs predominantly target coagulation pathways or platelets, often carrying high bleeding risks and showing limited efficacy against inflammation-associated VTE.
NETs play a crucial role in thrombosis, yet their regulatory mechanisms remain incompletely understood, and specific intervention strategies are currently lacking. Notably, prior studies suggested that inhibiting P2Y14R to limit neutrophil chemotaxis and excessive activation may benefit inflammatory thrombosis associated with infectious diseases like COVID-19. Against this backdrop, this study revealed significantly elevated P2Y14R expression in neutrophils from VTE patients. Using multiple knockout mouse models, the research team demonstrated that neutrophil-specific P2Y14R deficiency significantly suppressed NET release, alleviated venous thrombosis, and reduced inflammatory responses. Mechanistic studies revealed that P2Y14R deficiency activates PKA, promotes AKAP13 phosphorylation, inhibits RhoA activity and cytoskeletal reorganization, ultimately reducing neutrophil-platelet aggregation and NET formation. Further investigations revealed that the marketed drug clopidogrel is a high-affinity P2Y14R inhibitor (IC50 = 34.27 nM). In vivo and in vitro experiments confirmed that clopidogrel effectively inhibits NET release and alleviates thrombosis without increasing bleeding risk or impairing normal platelet aggregation, demonstrating promising drugability and safety. This study not only elucidates a novel mechanism of P2Y14R in VTE but also provides theoretical basis and candidate molecules for developing novel drugs with dual anti-inflammatory and anti-thrombotic effects (see figure below).
This research was supported by the National Natural Science Foundation of China (Grant Nos. 82373887; 82304506); Jiangsu Natural Science Foundation (No. BK20231022); Central Universities Basic Research Fund (No. 2632023GR23; No. 2632024TD01); and China Postdoctoral Science Foundation (No. 2022M723513).
