Liver injury is the first step in causing fibrosis, cirrhosis, and liver cancer, leading to mortality. However, the drivers of progressive liver injury are still incompletely defined. Here, we identify GBP5 as a major factor causing liver injury and inflammation. We show that the expression of GBP5 is abnormally elevated in the damaged liver, and its expression depends at least partially on the NF-κB-inducing kinase (NIK)/NF-κB2 signaling pathway. Knockout of Gbp5 ameliorates D-galactosamine/lipopolysaccharide (GalN/LPS)-induced liver injury and inflammation. Conversely, liver-specific overexpression of GBP5 induces liver injury and inflammation. Mechanistically, GBP5 induces hepatocyte apoptosis through the activation of both calpain/caspase 12/caspase 3 and TNFα/caspase 8/caspase 3 signaling pathways. Inhibition of either calpain activity or caspase 3 prevents GBP5-induced cell death. Our data demonstrate that GBP5 expression is induced by toxins or the NIK signaling pathway, which promotes both extrinsic and intrinsic apoptosis signaling pathways and further induces liver injury, providing a novel drug target for the treatment of liver injury and inflammation.
Keywords: GBP5; NF-κB-inducing kinase; apoptosis; caspase 3; liver injury.
© 2021 Federation of American Societies for Experimental Biology.