[Show abstract][Hide abstract] ABSTRACT: Wnt/β-catenin signaling plays an important role in hepatic homeostasis especially in liver development, regeneration and cancer, and loss of β-catenin signaling is often associated with increased apoptosis. To elucidate how β-catenin may be regulating hepatocyte survival, we investigated the susceptibility of β-catenin conditional knockout mice (KO) and littermate controls (WT) to Fas and TNF-α, two common pathways of hepatocyte apoptosis. While comparable detrimental effects from Fas activation were observed in WT and KO, a paradoxical survival benefit was observed in KO mice challenged with D-galactosamine (GalN)/lipopolysaccharide (LPS). KO showed significantly lower morbidity and liver injury due to early, robust and protracted activation of NF-κB in absence of β-catenin. Enhanced NF-κB activation in KO was contributed by increased basal inflammation and TLR4 expression and lack of p65-β-catenin complex in hepatocytes. β-Catenin-p65 complex in WT livers underwent temporal dissociation allowing for NF-κB activation to regulate hepatocyte survival following TNF-α-induced hepatic injury. Decrease of total β-Catenin protein but not its inactivation induced, while β-catenin stabilization either chemically or due to mutations repressed, p65 activity in hepatomas in a dose-dependent manner. Conclusion: β-Catenin-p65 complex in hepatocytes undergoes dynamic changes during TNFα-induced hepatic injury and plays a critical role in NF-κB activation and cell survival. Modulation of β-catenin levels is a unique mode of regulating NF-κB activity and thus may present novel opportunities in devising therapeutics in specific hepatic injuries. (HEPATOLOGY 2012.).