Gasdermin D aggravates a mouse model of radiation-induced liver disease by promoting chemokine secretion and neutrophil recruitment

Aoran Dong, Guangyan Wei, Zhou Liang, Yuqin Di, Yuhao Tang, Yunyan Ling, Shuping Li, Yong Chen, Yi Zhou (), Xiongjun Wang () and Zhenwei Peng ()
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Aoran Dong: Sun Yat-sen University
Guangyan Wei: Sun Yat-sen University
Zhou Liang: Sun Yat-sen University
Yuqin Di: Guangzhou
Yuhao Tang: Sun Yat-sen University
Yunyan Ling: Sun Yat-sen University
Shuping Li: Sun Yat-sen University
Yong Chen: Sun Yat-sen University
Yi Zhou: Sun Yat-sen University
Xiongjun Wang: Guangzhou University
Zhenwei Peng: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Radiation-induced liver disease (RILD) severely impairs the outcome of patients receiving irradiation (IR); however, its underlying mechanism remains unknown. GSDMD drives the progression of pyroptosis, and can be induced by IR in the gut and bone marrow, but its role in RILD remains unknown. Here we show that GSDMD is significantly upregulated and positively correlated with RILD severity in a mouse model. Hepatocytes are identified as critical pyroptotic cells in RILD thorough scRNA-seq, immunofluorescence and fluorescence-activated cell sorting analysis. Functional and mechanistic analysis using Gsdmd knockout (Gsdmd∆Hep) mice and cell models. Mechanistically, GSDMD is indispensable for triggering hepatocyte pyroptosis and initiating the activation of transcription factor STAT5A, which subsequently promoted CXCL1 expression to recruit neutrophil into liver to accelerate the severity of RILD. We also discovered that pharmacological targeting GSDMD and its downstream CXCL1 effectively alleviated RILD. Together, our study demonstrates that GSDMD as therapeutic targets to improve RILD.

Date: 2025
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DOI: 10.1038/s41467-025-61397-7

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