HMN 2026: What is the potential therapeutic target for alcohol-associated liver disease and alcohol use disorder

Scientists have identified a particular protein in the body that may influence the progression of alcohol-associated liver disease and drinking behavior. The protein aquaporin 9 (AQP9) helps liver cells absorb and excrete a byproduct of alcohol, which can be toxic to the body. The findings, published in Alcohol: Clinical and Experimental Research, point to AQP9 as a potential therapeutic target for the treatment of advanced liver disease and alcohol use disorder.

AQP9 proteins act like channels, helping cells absorb and secrete water-soluble substances. They’re found throughout the body but are concentrated in the liver. AQP9 has previously been shown to contribute to diabetes and liver disease due to its role in facilitating the entry of certain chemicals into the liver.

This study is the first to examine the role of AQP9 in the development of liver disease and alcohol use disorder through its channeling of acetaldehyde, or AcH, a toxin linked to liver damage and cancer that is produced when the body metabolizes alcohol. Researchers examined AQP9 levels in people with advanced liver disease and conducted multiple experiments in mice, some of which had been bred to lack the AQP9 protein.

The experiments demonstrated that AQP9 facilitates the entry of AcH into the liver and worsens early-stage alcohol-related liver damage. They also showed that the mice that did not have AQP9 were less likely to display binge-like alcohol consumption behaviors.

These mice had significantly delayed clearance of AcH from the liver and higher levels of AcH in their livers, blood, and brains, which would create aversive physical effects and likely influence consumption behaviors.

In human subjects, researchers found that AQP9 levels were significantly lower in people with alcohol-associated steatotic liver disease, and lower still in those with severe alcohol-associated hepatitis compared to people with healthy livers. These findings suggest that reduced AQP9 in the liver leads to increased death of liver cells and advanced liver disease due to prolonged toxicity from acetaldehyde.

The study reveals the previously unrecognized role of AQP9 in exacerbating cellular stress and inflammation in the liver due to alcohol metabolism, and provides direction for future research into the specific pathways in which AQP9 contributes to advanced liver disease.