Selonsertib, a Potential Drug for Liver Failure Therapy by Rescuing the Mitochondrial Dysfunction of Macrophage via ASK1-JNK-DRP1 Pathway

Abstract

BackgroundAcute liver failure (ALF) is associated with high mortality rate and there are still no effective treatments expect liver transplantation and artificial liver therapies. This study was aimed to determine the effects, therapeutic window and mechanisms of selonsertib, a selective inhibitor of ASK1, for ALF therapy.ResultsLipopolysaccharide and D-galactosamine (LPS/GalN) was used to simulate ALF. We found that selonsertib pretreatment significantly ameliorated ALF as determined by reduced hepatic necrosis and serum alanine aminotransferase, aspartate aminotransferase and inflammatory cytokine levels. However, selonsertib is only effective early after LPS/GalN administration and the limited therapeutic window was related to the activation and mitochondrial translocation of JNK and DRP1. Further experiments revealed that selonsertib could alleviate LPS-induced mitochondrial damage in macrophages by evaluating the mitochondrial membrane potential and mitochondrial permeability transition pore opening in macrophages. Selonsertib also suppressed the release of inflammatory cytokines from macrophages by reducing DRP1-mediated mitochondrial dysfunction, which was confirmed by using mdivi, the specific DRP1 inhibitor.ConclusionsSelonsertib protected against LPS/GalN-induced ALF by attenuating JNK-mediated DRP1 mitochondrial translocation and then rescuing mitochondrial damage in macrophages and may have therapeutic potential for early ALF patients.