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Fumarate hydratase acetylation by ethanol orchestrates mitochondrial DNA release and cGAS-STING-IRF3 mediated Hepatic stellate cell differentiation

ABSTRACT: Alcohol consumption is a major cause of liver fibrosis and further increases liver fibrosis due to other chronic liver diseases. Alcohol induces activation of hepatic stellate cells (HSC), the key fibrogenic cell of the liver, but the metabolic basis for this is not well understood. We identified that acetaldehyde, a metabolite of ethanol, induces lysine acetylation of mitochondrial fumarase (FH1), specifically in lysine residues K80 and K230 leading to reduced FH1 activity and accumulation of the substrate fumarate. The excess mitochondrial fumarate induced mitochondrial DNA (mtDNA) oxidation and release into the cytosol via formation of a mitochondrial permeability pore and voltage-dependent anion channel. The released mtDNA was observed to activate cGAS and subsequently the STING-IRF3 cascade. In a 6-week mouse model of alcohol diet, we observed that FH1 inhibition aggravated, while the STING inhibitor (IFM-004490-7) significantly blocked it. In conclusion, we observed that ethanol derived acetaldehyde mediated FH1 acetylation and subsequent inhibition result in the activation of HSC via the cGAS/STING/IRF3 pathway. This opens the possibility for novel therapeutic approaches to alleviate liver fibrosis by targeting FH1 acetylation and reducing its activity.

ORGANISM(S): Mus musculus

PROVIDER: GSE290734 | GEO | 2025/09/25

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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Fumarate hydratase acetylation by ethanol orchestrates mitochondrial DNA release and cGAS-STING-IRF3 mediated Hepatic stellate cell differentiation

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