GSDME-mediated Pyroptosis Contributes to Chemotherapy-induced Platelet Hyperactivity and Thrombotic Potential

• Cisplatin induces platelet pyroptosis via the activation of caspase-3-GSDME axis

• Flotillin-2 recruits GSDME-N to forms pores on platelet membranes, facilitating granule release and thus promoting platelet activation

Thrombotic complications due to platelet hyperreactivity are a major cause of death in patients undergoing chemotherapy. However, the underlying mechanisms are not fully understood. Herein, using human and GSDME^-/- mouse platelets, we showed that GSDME is functionally expressed in anucleate platelets and GSDME-mediated pyroptosis, a newly identified form of cell death in mammalian nucleated cells, contributes to platelet hyperactivity in cisplatin-based chemotherapy. Cisplatin or etoposide activates caspase-3 to cleave GSDME, thereby releasing the N-terminal fragment of GSDME (GSDME-N) toward the platelet plasma membrane, subsequently forming membrane pores and facilitating platelet granule release. This eventually promotes platelet hyperactivity and thrombotic potential. We identified flotillin-2, a scaffold protein, as a GSDME-N interactor that recruits GSDME-N to the platelet membrane. loss of GSDME protects mice from cisplatin-induced platelet hyperactivity. Our results provide evidence that targeting GSDME-mediated pyroptosis could reduce thrombotic potential in chemotherapy.