Abstract / Summary
Abstract Post-translational modifications (PTMs) are essential for hepatic protein function and signaling. While autophagy regulates the hepatic proteome through degradation and transcriptional control, its role in PTMs remains unclear. Using genetic and pharmacological models, we show that autophagy deficiency causes protein accumulation with increased ubiquitination, SUMOylation, methylation, and phosphorylation, but markedly reduces global protein acetylation—the hepatic acetylome—which is enhanced by autophagy activation. This acetylation loss results from decreased hepatic acetyl-CoA levels, independent of acetyltransferase or deacetylase expression. Mechanistically, NRF2 activation suppresses key acetyl-CoA biosynthetic enzymes (Acly, Acss, Mlycd, Pdha1), limiting substrate availability. Acetyl-CoA or acetate supplementation restores the protein acetylation and alleviates liver injury and inflammation in autophagy-deficient models. Similar reductions in acetylation and acetyl-CoA enzyme expression occur in preclinical models and human chronic liver disease. These findings identify a role for autophagy in regulating the hepatic protein acetylation through metabolic control of acetyl-CoA, with potential therapeutic implications.