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Acute liver failure (ALF) is characterized by sudden large area of inflammation and extensive hepatocyte apoptosis. This study identified the natural product berberine as a potential agent for acute liver failure(ALF). First, in vitro, BBR pre-incubation (5, 10 and 20 μM) alleviated L02 hepatocytes injury induced by D-GalN (5 mM)/TNF-α (100 ng/ml). Second, in vivo, BBR pre-treatment attenuated D-Galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver failure, as evidenced by the reduction of mortality, the alleviation of liver pathological changes and the inhibition of alanine aminotransferase (ALT)/aspartate aminotransferase (AST). Our results further illustrated that BBR inhibited the nuclear translocation of NF-κB p65 and subsequently suppressed the expressions of inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) at both mRNA and protein levels in ALF. Moreover, western blotting demonstrated that BBR effectively inhibited apoptosis via reducing cytochrome c release, Bax/Bcl-2 ratio and caspase-3/−9 cleavage in vitro and in vivo. In conclusion, our findings suggest that BBR serves as a potential agent for preventing or treating human ALF by inhibiting inflammation and mitochondria-dependent apoptosis.