AsianScientist (Aug. 27, 2025) – Alcohol-related liver disease (ALD) happens when someone drinks way too much alcohol. Since the liver helps in breaking down alcohol, drinking more than it can handle can seriously damage it.
About one in five cases of ALD progress to a more severe form called alcohol-associated steatohepatitis (ASH). This condition can eventually lead to liver scarring, also known as liver cirrhosis and even liver failure.
That’s why catching the disease early and starting treatment quickly is important to prevent it from getting worse. For a long time, doctors didn’t understand why some heavy drinkers develop liver problems while others don’t.
But recently, Korean researchers discovered the detailed molecular process that causes liver damage and inflammation from alcohol use. Their findings were published in the journal Nature Communications.
To figure out how alcohol drives ASH, the scientists tested different amounts of ethanol on liver cells called hepatocytes and in mice.
They used three different models: a single large ethanol dose, a 4.5% ethanol diet for two weeks, and two weeks of ethanol diet followed by a binge, which mimics chronic ASH in patients.
Through these experiments, they discovered a new mechanism where liver cells damaged by alcohol produce more reactive oxygen species (ROS), which can lead to cell death and trigger inflammation.
They also found that Kupffer cells, special immune cells in the liver, act as a kind of switch that can either ramp up or dial down inflammation, depending on their interactions with liver cells.
The research showed that when alcohol is consumed over a long period, the amount of VGLUT3, a glutamate transporter, increases in liver cells, causing glutamate to build up. Glutamate is an amino acid that usually helps with cell signaling and energy use, but in excess, it becomes toxic. Later, binge episodes cause calcium levels to spike, which then prompts glutamate to be released.
This glutamate activates mGluR5 receptors on Kupffer cells, which leads to more ROS production and a chain reaction that damages liver cells and sparks inflammation.
The scientists also discovered that damaged liver cells and Kupffer cells can form a direct contact point, similar to a synapse in the brain, which they call a “pseudosynapse.” This is a first-of-its-kind finding in liver biology, says the study. This contact allows the two cell types to communicate directly, sending distress signals rather than just dying passively.
That suggests that even outside the brain, direct cell-to-cell contact can transmit signals and that dying liver cells can both cause inflammation and trigger healing responses through this connection.
In tests with animals, blocking the activity of VGLUT3, mGluR5, or the enzyme NOX2, which produces ROS, helped reduce liver damage from alcohol. The same processes were confirmed in human ALD patients by analyzing blood and liver tissues.
“These findings may serve as new molecular targets for early diagnosis and treatment of ASH in the future,” said Won-Il Jeong, professor, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST).
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Source: Korea Advanced Institute of Science and Technology (KAIST) ; Image: Wey Wen Wong/ Asian Scientist Magazine
The study can be found at Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells
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