Gasdermin D protects against noninfectious liver injury by regulating apoptosis and necroptosis

Area of Science:

• Immunology
• Cell Biology
• Hepatology

Background:

• Gasdermin D (GsdmD) executes pyroptotic inflammatory cell death and is implicated in sepsis.
• Its role in noninfectious or sterile liver injury remains largely unknown.
• Understanding GsdmD's function in sterile injury is crucial for developing new therapeutic strategies.

Purpose of the Study:

• To investigate the role of GsdmD in noninfectious liver injury models.
• To determine GsdmD's contribution to liver damage following hemorrhagic shock with resuscitation (HS/R) and acetaminophen (APAP) overdose.
• To elucidate the mechanisms by which GsdmD influences cell death pathways in sterile liver injury.

Main Methods:

• Utilized wild-type (WT) and GsdmD knockout (GsdmD^-/-) mice.
• Induced liver injury using HS/R and APAP overdose models.
• Assessed liver damage via ALT levels, histological analysis, and measurement of cell death markers (apoptosis, necroptosis).
• Quantified caspase-8 cleavage and expression levels.

Main Results:

• GsdmD^-/- mice exhibited significantly increased liver damage and cell death after HS/R and APAP exposure compared to WT mice.
• In HS/R injury, GsdmD deficiency led to elevated caspase-8 cleavage and apoptosis.
• In severe APAP injury, GsdmD deficiency inhibited caspase-8 cleavage, resulting in increased necroptosis.

Conclusions:

• Gasdermin D plays a novel hepatoprotective role in noninfectious liver injury models.
• GsdmD regulates caspase-8 activation and downstream cell death pathways, with effects dependent on injury type and severity.
• Targeting the GsdmD/caspase-8 axis may offer a therapeutic approach for reactive oxygen species-mediated liver injury.