Integrated multi-omics reveals adaptive anti-oxidant remodeling in early alcohol-associated liver disease

Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality. Although various omics approaches have revealed early metabolic alterations, individual datasets provide limited mechanistic insight. Here, we integrated RNA sequencing with mass spectrometry–based analyses to quantify gene expression, protein abundance, proteome and acetylome dynamics, and metabolic fluxes in livers of alcohol-fed mice. This multi-layered approach revealed extensive metabolic rewiring characterized by suppressed mitochondrial energy metabolism and compensatory upregulation of glutathione (GSH) production, utilization, and recycling, establishing a high-flux antioxidant network. These changes were coupled to epigenetic histone H3 remodeling, marked by increased permissive acetylation and decreased suppressive methylation, linking alcohol-induced metabolic and redox alterations to chromatin reprogramming. ChEA-based in silico upstream transcription factor analysis, identified hepatocyte nuclear factor 4α (HNF4α) and nuclear factor erythroid 2–related factor 2 (NRF2) as key regulatory nodes. Alcohol exposure was associated with a modest HNF4α suppression alongside increased expression of NRF2, indicating a shift from HNF4α-driven metabolic programs toward NRF2-mediated antioxidant responses. Despite acetylation-associated impairment of mitochondrial proteins, GSH-related enzymes were preserved, supporting a protective, high-turnover antioxidant response that limits early oxidative stress and defines an adaptive state maintaining redox homeostasis while potentially predisposing to ALD progression.