Researchers at the University of Colorado Anschutz report that alcohol activates a metabolic pathway that generates fructose, which in turn fuels drinking behavior and liver injury in mice. The enzyme ketohexokinase (KHK) drives this process; inhibiting KHK reduced alcohol consumption and protected against liver damage in animal models.
A peer‑reviewed study published November 10, 2025, in Nature Metabolism links alcohol consumption to the body’s internal production of fructose via the polyol pathway, a process that depends on the enzyme ketohexokinase (KHK). The authors report that this fructose metabolism both reinforces alcohol‑seeking behavior and contributes to alcohol‑associated liver disease (ALD).
In behavioral experiments, mice lacking KHK drank less alcohol across multiple paradigms, including two‑bottle choice, conditioned place preference, and operant self‑administration. They also showed reduced activation of addiction‑related brain pathways, including lower ΔFosB expression in the nucleus accumbens, compared with controls. Pharmacologic inhibition of KHK likewise suppressed alcohol intake in mice, the paper reports.
Liver outcomes tracked with these behavioral effects. Under ethanol pair‑matched conditions, global and liver‑specific KHK knockout mice were protected from alcohol‑induced liver injury, with marked reductions in steatosis, inflammation, and fibrosis relative to controls. Press materials from CU Anschutz further state that liver injury did not develop when KHK was blocked either genetically or with a medication; the peer‑reviewed article specifically documents protection in genetic models and suppression of intake with pharmacologic inhibition.
“Our findings show that 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, an associate professor at CU Anschutz and senior author of the study. “By targeting fructose metabolism, we may be able to break this cycle and develop new treatments for both alcohol addiction and liver disease.”
The authors also note mechanistic overlap between ALD and metabolic dysfunction–associated steatotic liver disease (MASLD), both of which involve fructose‑dependent pathways. “This discovery highlights an unexpected intersection between sugar and alcohol metabolism,” said co‑author Richard Johnson, MD, a professor at CU Anschutz. “It opens exciting possibilities for developing treatments that target a common pathway underlying both metabolic and alcohol‑related liver diseases.”
The findings identify fructose metabolism—specifically, KHK activity—as a potential therapeutic target for alcohol use disorder (AUD) and related liver injury. Translation to humans will require clinical studies to determine whether KHK inhibition can safely and effectively reduce harmful drinking and prevent liver damage outside of animal models.
