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

作者：Aoran Dong, Guangyan Wei, Liang Shou Zhou, Yuqin Di, Yuhao Tang, Yunyan Ling, Shuping Li, Yong Chen, Yi Zhou, Xiongjun Wang, Zhenwei Peng · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61397-7 · 被引用次数：5 · 研究领域：Inflammasome and immune disorders、Immune Response and Inflammation、Effects of Radiation Exposure

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. Radiation-induced liver damage is an important side-effect of radiation as a cancer therapy. Here, the authors identify pyroptosis protein gasdermin D as a key driver of liver injury and a potential therapeutic target to alleviate this damage.