Keap1 Deletion Rescues Cell Death Associated With Gpx4 Loss in Hepatocytes During Acute Liver Injury

Area of Science:

• Hepatology and molecular biology
• Cell death pathways
• Oxidative stress and antioxidant defense

Background:

• Acute liver failure (ALF) is a severe condition with limited therapeutic options.
• Elevated reactive oxygen species (ROS) contribute to hepatocyte death in ALF.
• Nuclear factor erythroid-2 like 2 (Nrf2) regulates antioxidant genes, including glutathione peroxidase 4 (GPX4), which prevents lipid peroxidation (LPO) and is involved in apoptosis and ferroptosis.

Purpose of the Study:

• To investigate the role of GPX4 in ALF.
• To explore the therapeutic potential of the Keap1-Nrf2 pathway in ALF.

Main Methods:

• Measured GPX4 expression in human liver samples (healthy, ALF, ACLF).
• Generated mice with hepatocyte-specific Gpx4 deletion (Gpx4^Δhepa) and combined Gpx4/Keap1 deletion (Gpx4^ΔhepaKeap1^Δhepa).
• Induced ALF in mice using carbon tetrachloride (CCl₄) and bile duct ligation (BDL) models.

Main Results:

• ALF patients and CCl₄-treated wild-type mice showed reduced GPX4 levels.
• Gpx4^Δhepa mice exhibited increased hepatocyte death and apoptosis upon CCl₄ induction.
• Nrf2 activation in Gpx4^ΔhepaKeap1^Δhepa mice reduced liver damage, necrosis, and apoptosis, inducing BCL2.

Conclusions:

• GPX4 deficiency exacerbates apoptosis in ALF.
• Activating Keap1-dependent pathways and upregulating BCL2 protects against ALF in Gpx4-deficient mice.
• The Keap1-Nrf2 axis represents a potential therapeutic target for ALF.