Our current study demonstrates (1) that GSK3β is activated in the acute phase of ALF, and inhibition GSK3β can ameliorate the toxin induced liver failure, suggesting its clinical potentials, (2) that the role of GSK3β in ALF may act upstream or modulate the major MAPK pathways and by induction of pro-inflammatory cytokines, (3) that GSK3β may either act modulate TLR4 expression in amplification of injury signals, and (4) that activation GSK3β may control ERS and its dependent apoptosis in ALF. Here, TLR4 is linked to liver failure.