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XBP1 deficiency promotes hepatocyte pyroptosis by impairing mitophagy to activate mtDNA-cGAS-STING signaling in macrophages during acute liver injury
Lack of XBP1 increases liver cell death by blocking damaged mitochondria cleanup, triggering immune activation in liver injury
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Abstract
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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