GSDMD induces hepatocyte pyroptosis to trigger alcoholic hepatitis through modulating mitochondrial dysfunction.

Area of Science:

• Hepatology
• Immunology
• Cellular Biology

Background:

• Mechanisms linking Gasdermin D (GSDMD) activation to alcoholic hepatitis (AH) remain poorly understood.
• Investigating the role of GSDMD in alcohol-induced hepatocyte pyroptosis and mitochondrial dysfunction is crucial for understanding AH pathogenesis.

Purpose of the Study:

• To determine if GSDMD activation induces hepatocyte pyroptosis by regulating mitochondrial dysfunction in alcoholic hepatitis.
• To explore the therapeutic potential of targeting GSDMD and mitochondrial pathways in AH.

Main Methods:

• Assessment of liver damage using histology and serum biomarkers (AST, ALT, TC, TG).
• Quantification of pyroptosis markers (IL-1β, IL-18, LDH, inflammasome proteins, hepatocyte death).
• Evaluation of mitochondrial function (mtDNA, ROS, membrane potential, ATP, protein levels, morphology) and GSDMD/Drp1 expression.

Main Results:

• Alcoholic hepatitis induced GSDMD activation, increasing liver GSDMD-N, NLRP3, and Caspase 11 expression.
• GSDMD inhibition alleviated alcohol-induced hepatocyte pyroptosis and liver injury.
• Alcohol-induced mitochondrial dysfunction was improved by GSDMD inhibition, and enhancing mitochondrial function suppressed pyroptosis.

Conclusions:

• Gasdermin D (GSDMD) mediates hepatocyte pyroptosis by modulating mitochondrial dysfunction in alcoholic hepatitis.
• These findings highlight GSDMD and mitochondrial pathways as potential therapeutic targets for alcoholic hepatitis.