Selonsertib, a potential drug for liver failure therapy by rescuing the mitochondrial dysfunction of macrophage via ASK1–JNK–DRP1 pathway

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