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

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.