Overview

• Chronic alcohol exposure upregulates the vesicular glutamate transporter VGLUT3 in hepatocytes, leading to glutamate accumulation
• Binge drinking triggers calcium-dependent glutamate secretion that activates mGluR5 on Kupffer cells and drives NOX2-mediated ROS production, causing hepatocyte death and inflammation
• Researchers identified brain-like pseudosynaptic contacts between damaged hepatocytes and Kupffer cells that enable direct glutamate signaling and immune cell modulation
• Kupffer cells act as dual-function regulators capable of switching between pro-inflammatory and anti-inflammatory roles in response to hepatocyte distress signals
• Genetic or pharmacological inhibition of VGLUT3, mGluR5 or NOX2 reduces liver damage in animal models and human ASH samples, offering molecular targets for early diagnosis and therapy