Tyrphostin AG538 inhibits platelet activation and thrombosis via TREM2 agonism

Arterial thrombotic diseases remain a major threat to human health. Given the critical role of platelets in thrombus formation, dysregulated platelet activity can result in either hemorrhagic or ischemic complications. Although current antiplatelet therapies are effective, their use is often limited by bleeding risks, highlighting the need for novel antiplatelet agents that can prevent thrombosis with minimal hemostatic disruption. We recently reported that TREM2 (triggering receptor expressed on myeloid cells 2) as a negative regulator of platelet activation and thrombosis. In this study, we demonstrate that Tyrphostin AG538 functions as a platelet TREM2 receptor agonist. Molecular docking, SPR (surface plasmon resonance) assay, and experiments using platelets from TREM2 knockout mice confirm that AG538 directly binds TREM2. AG538 inhibited platelet aggregation, dense granule release of human and mouse platelets, and impaired platelet spreading and clot retraction. Oral administration of AG538 suppressed collagen-induced platelet activation in mice. Moreover, AG538 significantly reduced arterial thrombus formation in mesenteric arteriole injury model and alleviated pulmonary embolism, without increasing bleeding. Mechanistically, as a TREM2 agonist, AG538 inhibits the downstream SHIP1 (Src homology 2 (SH2) domain-containing inositol 5-phosphatase 1)-Akt pathway. These findings suggest that AG538 may be a promising antiplatelet antithrombotic agent with a favorable safety profile.