A novel noncanonical Src-mammalian STE20-like kinase 1 (MST1)-Akt/glycogen synthase kinase-3β (GSK3β) pathway drives platelet activation and thrombosis.

BACKGROUND

The Hippo pathway kinase mammalian sterile 20-like kinase 1 (MST1), also known as serine/threonine kinase 4, has been extensively studied in nucleated cells, but its role in platelet activation and thrombosis remains unclear.

OBJECTIVES

To investigate the role of MST1 in platelet activation, thrombosis, and acute coronary syndrome (ACS), and to evaluate its potential as an antiplatelet target.

METHODS

Platelet-specific Mst1 deletion mice and the MST1/2 inhibitor XMU-MP-1 were used to evaluate the role of MST1 in platelet function, mesenteric arterial thrombosis, pulmonary embolism, and hemostasis. Protein interactions were analyzed by coimmunoprecipitation, and clinical relevance was evaluated using platelets from patients with ACS and a mouse model of experimental myocardial infarction.

RESULTS

Platelet-specific Mst1 deletion impaired mouse platelet aggregation, adenosine triphosphate release, spreading, clot retraction, and platelet adhesion, as assayed in a flow chamber; it also inhibited thrombus formation in mouse mesenteric arterioles and in pulmonary embolism without increasing bleeding risk. Consistently, MST1/2 inhibition with XMU-MP-1 suppressed platelet activation and thrombosis, with efficacy comparable to aspirin but without prolonging bleeding time. Mechanistically, MST1 associated with Src and Akt, and its deletion or inhibition reduced Akt and phosphorylation during platelet activation, revealing a Src-MST1-Akt/glycogen synthase kinase-3β signaling axis. MST1 expression was elevated in platelets from ACS patients, whereas platelet-specific Mst1 deletion reduced experimental myocardial infarction and improved cardiac function in mice.

CONCLUSION

MST1 mediates platelet activation and thrombosis. Genetic deletion of Mst1 or pharmacological inhibition with XMU-MP-1 suppresses thrombotic responses without impairing hemostasis, supporting MST1 as an antiplatelet target with reduced bleeding liability.