Zinc ions inhibit migrasome biogenesis and impair platelet function by targeting cholesterol and sphingomyelin

Aim: Zinc ions are critical regulators of cellular homeostasis and hemostasis. Migrasomes promote thrombus formation, yet whether zinc ions influence migrasome biogenesis and the associated thrombotic outcomes remains unexplored. This work therefore examined how zinc ions affect migrasome formation and assessed the functional consequences for platelet aggregation and bleeding volume. Methods: We performed RNA sequencing on Huh7.5.1 cells treated with ZnSO4 or zinc gluconate. Migrasome formation was evaluated in both these cells and in mouse whole blood, while intracellular zinc levels were manipulated using disulfiram to enhance efflux or anti-solute carrier family 39 member 6 (SLC39A6) antibodies to inhibit uptake. Migrasomes were visualized through immunofluorescence with wheat germ agglutinin (WGA). Changes in cholesterol, sphingomyelin and reactive oxygen species (ROS) levels in response to zinc ions were measured. Migrasomes were isolated from mouse blood using a specialized isolation kit. Results: Zinc ions treatment reduced migrasome numbers in both cellular and whole-blood models in a dose-dependent manner. Zinc ions also decreased cholesterol, sphingomyelin, and ROS levels and impaired migrasome biogenesis. In mice, zinc administration reduced platelet counts and aggregation while increasing bleeding volume. Conclusion: Our findings demonstrate that zinc ions modulate migrasome formation by lowering cholesterol levels, thereby negatively regulating platelet aggregation. This research enhances the current understanding of trace element biology and suggests that modulating zinc ion levels could be a potential therapeutic strategy for managing hemostatic disorders.