Identification of a common ketohexokinase-dependent link driving alcohol intake and alcohol-associated liver disease in mice

Abstract Alcohol and sugar share reinforcing properties and both contribute to liver disease progression, ultimately leading to cirrhosis. Emerging evidence suggests that ethanol activates the aldose reductase pathway, resulting in endogenous fructose production. Here we investigated whether alcohol preference and alcohol-associated liver disease (ALD) are mediated through fructose metabolism by ketohexokinase (KHK)-A/C. Using global, conditional and tissue-specific KHK-A/C knockout mice, we assessed ethanol intake, reinforcement behaviours and liver injury. Ethanol consumption increased portal vein osmolality and activated the polyol pathway in the liver and intestine, leading to fructose production metabolized by KHK-A/C. Mice lacking KHK-A/C showed reduced ethanol preference across multiple paradigms, including two-bottle choice, conditioned place preference and operant self-administration, alongside decreased ∆FosB expression in the nucleus accumbens. Both genetic deletion and pharmacologic inhibition of KHK-A/C suppressed ethanol intake. Hepatocyte-specific KHK-A/C knockout mice displayed partially reduced alcohol consumption, potentially linked to altered aldehyde dehydrogenase expression, while intestinal KHK-A/C deletion restored glucagon-like peptide-1 levels—a hormone known to suppress alcohol intake. Under ethanol pair-matched conditions, global and liver-specific KHK-A/C knockout mice were protected from ALD, with marked reductions in hepatic steatosis, inflammation and fibrosis. These findings identify ethanol-induced fructose metabolism as a key driver of excessive alcohol consumption and ALD pathogenesis. Given that ALD and metabolic dysfunction-associated steatotic liver disease share fructose-dependent mechanisms, targeting fructose metabolism may offer a novel therapeutic approach for treating alcohol use disorder and related liver injury.