Lack of XBP1 increases liver cell death by blocking damaged mitochondria cleanup, triggering immune activation in liver injury

XBP1 deficiency leads to exacerbated acute liver injury (ALI) with increased hepatocellular pyroptosis and enhanced macrophage STING activation.

• Hepatocyte-specific XBP1 knockout mice exhibit worsened ALI when compared to normal mice.
• TAA-induced stress results in the release of mitochondrial DNA (mtDNA) from damaged hepatocytes, which activates macrophage STING signaling.
• Increased production of reactive oxygen species (ROS) is associated with XBP1 deficiency, promoting hepatocellular pyroptosis via specific signaling pathways.
• Impaired mitophagy in XBP1 deficient hepatocytes contributes to the activation of macrophages and may be reversed through PINK1 overexpression.
• Observations in human livers with ALI indicate a similar activation of XBP1-mediated pathways.

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