IDH1/MDH1 deacetylation activates the cGAS-STING pathway by promoting NETosis in acute liver failure

Background: Acute liver failure (ALF) is a life-threatening disease caused by multiple factors. Our previous study shows that IDH1/MDH1 deacetylation aggravates ALF through NETosis (a new mode of cell death). However, the exact mechanism by which NETosis mediates ALF is still unclear.

Methods: The transcriptome Sequencing data of hepatic tissues from ALF mice and healthy control mice were downloaded from the GEO database. Inflammation-related pathways of ALF were identified by differential expression analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. In vivo, a mouse ALF model was established with LPS/D-gal. In vitro, HepG2 cells were used to simulate hepatocyte injury. The cell death rate of HepG2 cells was detected by flow cytometry. The levels of inflammatory factors in mouse liver tissues were detected by enzyme-linked immunosorbent assay (ELISA). The formation of NETs and the levels of cGAS-STING pathway-related proteins were detected by Western blotting, immunohistochemistry and immunofluorescence.

Results: The cGAS-STING pathway was activated in LPS/D-gal-induced ALF. In the ALF mouse model, ACY1215, as a histone deacetylase 6 inhibitor, alleviated ALF by inhibiting cGAS-STING pathway. Deoxyribonuclease 1 (DNase 1) degraded NETs formed by IDH1/MDH1 deacetylation in mouse liver tissue. DNase 1 attenuated hepatic tissue injury, reduced serum ALT and AST levels and reduced the levels of TNF-α and IL-6 in liver tissues. IDH1/MDH1 deacetylation increased the levels of cGAS-STING pathway-related protein, which was reversed by DNase 1. Exogenous NETs enhanced LPS/D-gal-induced hepatocyte death and activation of the cGAS-STING pathway in vitro.

Conclusion: IDH1/MDH1 deacetylation activates the cGAS-STING signaling pathway by NETs. The activation of STING promotes pro-inflammatory cytokine production and exacerbates the inflammatory response in LPS/D-gal-induced ALF.

Acute liver failure; Deacetylation; NETosis; cGAS-STING pathway.