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The N-terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism

ABSTRACT: Background: The increasing prevalence of chronic liver disease has become a significant global health concern. Pyroptosis leads to cell rupture, releasing large amounts of pro-inflammatory cellular contents and promoting the progression of liver fibrosis. Therefore, targeting pyroptosis may serve as a new strategy for the treatment of chronic liver diseases. Methods: We constructed GSDMD-NTki/wt & Alb-creki/wt mice using CRISPR/Cas9 gene editing technology and induced conditional cell death by doxycycline to construct a mouse model of liver fibrosis. We analyzed differentially expressed genes by RNA sequencing and explored their biological functions. Obeticholic acid was used to assess the modeling effects of fibrosis. Results: Doxycycline-treated GSDMD-NTki/wt & Alb-creki/wt mice showed severe liver damage, vacuolation of hepatocytes, increased collagen fibers, accumulation of lipid droplets, and much stronger expression of genes involved in liver fibrosis development in the liver compared with untreated mice. RNA-sequencing showed that upregulated differentially expressed genes in the GSDMD-NTki/wt & Alb-creki/wt doxycycline-treated group were involved in inflammatory responses, cell activation, and metabolic processes. Obeticholic acid was used to assess the modeling effects of fibrosis. Obeticholic acid treatment of GSDMD-NTki/wt & Alb-creki/wt mice reduced ALT and AST levels, and enhanced anti-fibrotic effects were observed. Conclusions: Our results demonstrated that we successfully constructed a mouse model of liver fibrosis, and GSDMD-NT induced fibrosis by mediating lipid metabolism.

ORGANISM(S): Mus musculus

PROVIDER: GSE252989 | GEO | 2025/01/11

REPOSITORIES: GEO

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Project description:Background and Aims: The activation of stimulator of interferon genes (STING) and NOD-like receptors protein 3 (NLRP3) inflammasomes-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnection between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown and is the focus of this study. Approach and Results: Liver fibrosis was induced in Sting knockout, Gasdermin D (Gsdmd) knockout mice, and in mice with hepatocyte-specific Nlrp3 deletion. RNA-sequencing, metabolomics, epigenetic compound screening system, and chromatin immunoprecipitation were utilized. STING and NLRP3 inflammasome signaling pathways were activated in cirrhotic livers but were suppressed by Sting knockout. Sting knockout also ameliorated hepatic pyroptosis, inflammation, and fibrosis in the murine cirrhotic model. In vitro, STING induced pyroptosis in primary murine hepatocytes via activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) were identified to regulate NLRP3 expression in STING-overexpressed AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhanced interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promoted STING-induced Nlrp3 transcription in hepatocytes. The RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes showed that metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gsdmd knockout attenuated hepatic pyroptosis, inflammation, and fibrosis in murine cirrhotic models. Conclusions: This study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.

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The N-terminal domain of gasdermin D induces liver fibrosis by reprogrammed lipid metabolism

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