The progression of hepatocyte pyroptosis exacerbates radiation-induced liver disease via the gasdermin D/signal transducer and activator of transcription 5a/CXCL1 axis

Abstract

Abstract Radiation-induced liver disease (RILD) severely impairs the outcome of patients exposed to irradiation (IR); however, the underlying mechanism is largely unknown. The N-terminus of gasdermin D (GSDMD-N) is mainly involved in driving the progression of pyroptosis, and its expression has been reported to be induced by IR in the gut and bone marrow, but its role in RILD remains unknown. By collecting liver samples from RILD patients and mice, we uncovered GSDMD-FL/N were significantly upregulated and positively correlated with RILD severity. Hepatocytes are found to be critical pyroptotic cells in RILD by combining single-cell RNA sequencing (scRNA-seq), immunofluorescence and fluorescence-activated cell sorting (FACS) analysis. Functional analysis and mechanistic studies were performed using hepatocyte-specific Gsdmd knockout (Gsdmd∆Hep) mice and cell models and scRNA-seq analysis. Mechanistically, GSDMD was indispensable for triggering hepatocyte pyroptosis and initiating the activation of transcription factor stat5a, which subsequently facilitated the expression of CXCL1. As a pore-forming protein, increased GSDMD-N also mediated the secretion of CXCL1, which further recruited neutrophil into liver to accelerate the severity of RILD. We also discovered that pharmacological targeting GSDMD and its downstream CXCL1 effectively attenuated the progression of RILD. RILD progression requires increased GSDMD-FL/N in hepatocytes, causing pyroptosis and stat5a activation. Afterwards, driving CXCL1 express and release to recruit neutrophils into liver. Together, our study demonstrates that GSDMD as therapeutic targets to improve RILD.