GSDME-mediated pyroptosis contributes to chemotherapy-induced platelet hyperactivity and thrombotic potential

作者：Ruyi Xue, Min� Li, Ge Zhang, Wei Zhang, Liping Han, Bo Tao, Haoxuan Zhong, Dingjin Yao, Yiran Deng, She Chen, Si Zhang · 发表于：Blood · 年份：2024 · DOI：10.1182/blood.2023023179 · 被引用次数：15 · 研究领域：Inflammatory Biomarkers in Disease Prognosis、Caveolin-1 and cellular processes、Erythrocyte Function and Pathophysiology

ABSTRACT: 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 platelets and platelets from mice lacking gasdermin E (GSDME), we show that GSDME is functionally expressed in anucleate platelets, and that 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.