For decades, researchers have searched for the biological roots of alcohol addiction and the damage it leaves behind. Now, a team at the University of Colorado Anschutz Medical Campus has found that both might hinge on the same surprising target: an enzyme better known for processing sugar.
The study, published in Nature Metabolism, shows that alcohol consumption activates a pathway in the body that converts glucose into fructose. This process, powered by the enzyme ketohexokinase (KHK), appears to encourage drinking behavior while worsening alcohol-associated liver disease (ALD). When KHK was blocked in mice, alcohol cravings dropped, and liver damage all but disappeared.
“Alcohol doesn’t just damage the liver directly, it hijacks the body’s sugar metabolism in a way that enhances drinking behavior and worsens liver injury,” said Miguel A. Lanaspa, DVM, PhD, associate research professor and senior author.
The researchers found that alcohol increases internal fructose production through the polyol pathway, a metabolic process that typically helps cells manage osmotic stress. Fructose produced this way is then metabolized by KHK, leading to fat buildup, inflammation, and fibrosis in the liver. When the scientists genetically deleted or pharmacologically inhibited KHK, these effects vanished.
From Sugar Craving to Alcohol Dependence
Both sugar and alcohol stimulate dopamine release and activate reward circuits in the brain. In mice, removing KHK reduced these neural responses, suggesting that fructose metabolism directly reinforces alcohol’s addictive potential. The KHK-deficient mice showed lower alcohol preference across multiple behavioral tests and lacked molecular markers of addiction in the nucleus accumbens, the brain’s reward hub.
The connection between fructose and alcohol was so strong that even the absence of a related enzyme, aldose reductase (AR)—which kickstarts endogenous fructose production—produced similar effects. Mice lacking AR drank less alcohol over time, confirming that alcohol’s influence on sugar pathways feeds back into its own consumption.
The findings also linked liver metabolism to alcohol preference. In mice engineered to lack KHK only in the liver, ethanol metabolism slowed, acetaldehyde detoxification faltered, and the brain’s reward response to alcohol diminished. At the same time, their livers resisted fat accumulation, inflammation, and scarring that normally follow long-term alcohol exposure.
The Gut–Brain Connection and a Therapeutic Horizon
The team also discovered that ethanol suppresses the hormone GLP-1, a gut-derived peptide known to reduce alcohol intake. When KHK was blocked in the intestine, GLP-1 levels rebounded, and alcohol consumption dropped. This gut-brain hormonal loop may partly explain why sugar and alcohol cravings often overlap.
“This discovery highlights an unexpected intersection between sugar and alcohol metabolism,” said Richard Johnson, MD, professor and study co-author. “It opens exciting possibilities for developing treatments that target a common pathway underlying both metabolic and alcohol-related liver diseases.”
Pharmacological tests using a KHK inhibitor, CRP427, confirmed these results. High-drinking mice and rats treated with the compound voluntarily consumed less alcohol, mirroring the genetic models. The compound’s ability to penetrate the liver and block fructose metabolism suggests a realistic path for future drug development.
Because fructose metabolism also underlies diet-induced liver disease, these findings extend beyond addiction. Targeting KHK could benefit patients with either alcohol-associated or metabolic steatotic liver disease (MASLD), both of which involve fat accumulation and inflammation driven by fructose metabolism.
Though the study was conducted in animals, its authors note that similar pathways have been observed in humans with ALD, where both aldose reductase and hepatic fructose levels are elevated. The next step, they say, is to explore whether inhibiting KHK can safely reduce alcohol consumption and prevent liver damage in people.
The research underscores how two of humanity’s oldest vices—sugar and alcohol—may be more biologically intertwined than anyone imagined. By cutting off the enzyme that bridges them, scientists may have found a way to blunt both craving and harm at their metabolic source.