The role of astrocytic GSDME in Sepsis-associated cognitive dysfunction.

Abstract

Sepsis-associated encephalopathy (SAE) is a neurofunctional disorder resulting from sepsis, primarily manifested as acute brain dysfunction and long-term cognitive decline. This study utilizes the cecal ligation and puncture (CLP) model to investigate the role of Gasdermin E (GSDME)-mediated pyroptosis in hippocampal astrocytes in the pathogenesis of SAE-related cognitive dysfunction, as well as the therapeutic potential of geniposide, an active compound from the traditional Chinese medicine formula An-gong Niu-huang pill (Ag-NhP). Our results demonstrate that CLP significantly upregulates GSDME expression and cleavage in hippocampal astrocytes, which contributes to cognitive dysfunction in mice. Notably, astrocyte-specific knockdown of GSDME markedly alleviates cognitive impairment in septic mice, highlighting the critical role of GSDME-mediated pyroptosis in SAE. Further, we identified geniposide as an active component of Ag-NhP that inhibits GSDME-mediated pyroptosis. Geniposide not only inhibits GSDME activation but also prevents the translocation of cleaved GSDME to the cell membrane. In vivo, geniposide administration significantly improves cognitive dysfunction induced by SAE. In conclusion, our findings reveal that GSDME-mediated astrocytic pyroptosis in the hippocampus plays a pivotal role in the development of cognitive dysfunction, and that geniposide effectively inhibits this process, offering potential therapeutic benefits for SAE-induced cognitive impairment.