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

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.