KAIST

<(From left)Dr. Keungmo Yang, Professor Won-Il Jeong, Ph.D candidate Kyurae Kim>

Excessive alcohol consumption causes alcoholic liver disease, and about 20% of these cases progress to alcohol-associated steatohepatitis (ASH), which can lead to liver cirrhosis and liver failure. Early diagnosis and treatment are therefore extremely important. A KAIST research team has identified a new molecular mechanism in which alcohol-damaged liver cells increase reactive oxygen species (ROS), leading to cell death and inflammatory responses. In addition, they discovered that Kupffer cells, immune cells residing in the liver, act as a “dual-function regulator” that can either promote or suppress inflammation through interactions with liver cells.

KAIST (President Kwang-Hyung Lee) announced on the 17th that a research team led by Professor Won-Il Jeong from the Graduate School of Medical Science and Engineering, in collaboration with Professor Won Kim’s team at Seoul National University Boramae Medical Center, has uncovered the molecular pathway of liver damage and inflammation caused by alcohol consumption. This finding offers new clues for the diagnosis and treatment of alcohol-associated liver disease (ALD).

Professor Won-Il Jeong’s research team found that during chronic alcohol intake, expression of the vesicular glutamate transporter VGLUT3 increases, leading to glutamate accumulation in hepatocytes. Subsequent binge drinking causes rapid changes in intracellular calcium levels, which then triggers glutamate* secretion. The secreted glutamate stimulates the glutamate receptor mGluR5 on liver-resident macrophages (Kupffer cells), which induces ROS production and activates a pathological pathway resulting in hepatocyte death and inflammation.
 *Glutamate: A type of amino acid involved in intercellular signaling, protein synthesis, and energy metabolism in various tissues including the brain and liver. In excess, it can cause overexcitation and death of nerve cells.

 <Figure1. Glutamate accumulation in perivenous hepatocytes through vesicular glutamate transporter 3 after 2-week EtOH intake and its release by binge drinking>

A particularly groundbreaking aspect of this study is that damaged hepatocytes and Kupffer cells can form a "pseudosynapse"—a structure similar to a synapse which is previously thought to occur only in the brain—enabling them to exchange signals. This is the first time such a phenomenon has been identified in the liver.

This pseudosynapse forms when hepatocytes expand (ballooning) due to alcohol, becoming physically attached to Kupffer cells. Simply put, the damaged hepatocytes don’t just die—they send distress signals to nearby immune cells, prompting a response.

This discovery proposes a new paradigm: even in peripheral organs, direct structural contact between cells can allow signal transmission. It also shows that damaged hepatocytes can actively stimulate macrophages and induce regeneration through cell death, revealing the liver’s “autonomous recovery function.”

The team also confirmed in animal models that genetic or pharmacological inhibition of VGLUT3, mGluR5, or the ROS-producing enzyme NOX2 reduces alcohol-induced liver damage. They also confirmed that the same mechanism observed in animal models was present in human patients with ALD by analyzing blood and liver tissue samples.

<Figure2. Binge drinking rapidly alters the intracellular calcium levels to release glutamates and activate mGluR5 of Kupffer cells>

Professor Won-Il Jeong of KAIST said, “These findings may serve as new molecular targets for early diagnosis and treatment of ASH in the future.”

This study was jointly led by Dr. Keungmo Yang (now at Yeouido St. Mary’s Hospital) and Kyurae Kim, a doctoral candidate at KAIST, who served as co–first authors. It was conducted in collaboration with Professor Won Kim’s team at Seoul National University Boramae Medical Center and was published in the journal Nature Communications on July 1.

※ Article Title: Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells
 ※ DOI: https://doi.org/10.1038/s41467-025-60820-3

This study was supported by the Ministry of Science and ICT through the National Research Foundation of Korea's Global Leader Program, Mid-Career Researcher Program, and the Bio & Medical Technology Development Program.