KIRA8 attenuates non-alcoholic steatohepatitis through inhibition of the IRE1a/XBP1 signalling pathway

Endoplasmic reticulum (ER) stress is enhanced in non-alcoholic steatohepatitis (NASH). Among three signalling pathways, the IRE1a/XBP1 signalling pathway is strongly implicated in the pathogenesis of NASH but its significance is still largely uncharacterised. In this report, we constructed a hepatocyte-specific XBP1-Luciferase knock-in mouse model that allows in vivo monitoring of the IRE1a/XBP1 ac-tivity in hepatocytes. Using this mouse model, we found that IRE1a/XBP1 was activated within hepa-tocytes during the pathogenesis of NASH. Significantly, a specific IRE1a kinase-inhibiting RNase attenuator, KIRA8, attenuated NASH in mice. In conclusion, our hepatocyte-specific XBP1 splicing re-porter mouse represents a valid model for research and drug development of NASH, which showed that the IRE1a-induced XBP splicing is potentiated in hepatocytes during pathogenesis of NASH. Furthermore, we carried out the proof-of-concept study to demonstrate that the allosteric IRE1a RNase inhibitor serves as a promising therapeutic agent for the treatment of NASH.(c) 2022 Elsevier Inc. All rights reserved.