Alcohol-dependent Regulation of the Energy Metabolism in Hepatocytes by the Deubiquitinase A20 after Trauma

Trauma induces a hyperinflammatory and hypermetabolic state that places substantial energetic demands on the liver. Acute alcohol intoxication (AEI), frequently present in trauma patients, is associated with aggravated hepatic dysfunction. The metabolic mechanisms underlying this interaction remain poorly defined. The deubiquitinase A20, a negative regulator of NF-κB signaling, may play a role in coordinating inflammatory and metabolic responses. This study examined how trauma-like inflammatory stimulation and AEI alter hepatocellular metabolism and whether A20 shapes these responses. Human HepG2 cells and primary murine hepatocytes with hepatocyte-specific A20 deletion were stimulated with a polytrauma cocktail (PTC) in the presence or absence of ethanol or its metabolite acetaldehyde. Mitochondrial and glycolytic ATP production, oxygen consumption, mitochondrial membrane potential, and gene expression of metabolic regulators were assessed to characterize bioenergetic adaptations. PTC induced an energetically demanding metabolic activation, reflected by increased respiration and ATP production, accompanied by signs of mitochondrial strain. Acute alcohol exposure suppressed this trauma-induced oxidative response and shifted ATP production toward glycolysis, indicating reduced metabolic flexibility. A20 deficiency amplified metabolic activation under trauma-like conditions, suggesting a role for A20 as a metabolic checkpoint that limits excessive mitochondrial drive. However, the presence of alcohol overrode A20-mediated regulation, resulting in a similarly suppressed oxidative phenotype in both genotypes. These findings demonstrate that trauma triggers a high-output but inefficient oxidative program in hepatocytes, while alcohol imposes a dominant metabolic brake. Targeting redox–mitochondrial regulation may offer therapeutic potential in alcohol-complicated trauma.