Xue Ruyi, Li Min, Zhang Ge, Zhang Wei, Han Liping, Bo Tao, Zhong Haoxuan, Yao Dingjin, Deng Yiran, Chen She, Zhang Si
Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
Blood. 2024 Dec 19;144(25):2652-2665. doi: 10.1182/blood.2023023179.
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.
血小板高反应性导致的血栓并发症是化疗患者死亡的主要原因。然而，其潜在机制尚未完全明确。在此，我们使用人血小板以及缺乏gasdermin E（GSDME）的小鼠的血小板，发现GSDME在无核血小板中功能性表达，并且GSDME介导的焦亡（一种在哺乳动物有核细胞中新发现的细胞死亡形式）在基于顺铂的化疗中导致血小板活性亢进。顺铂或依托泊苷激活caspase-3以切割GSDME，从而将GSDME的N端片段（GSDME-N）释放至血小板质膜，随后形成膜孔并促进血小板颗粒释放。这最终促进血小板活性亢进和血栓形成潜能。我们鉴定出一种支架蛋白flotillin-2作为GSDME-N相互作用分子，其将GSDME-N募集至血小板膜。GSDME缺失可保护小鼠免受顺铂诱导的血小板活性亢进影响。我们的结果表明，针对GSDME介导的焦亡可能降低化疗中的血栓形成潜能。
