AIM: To investigate the role of protein kinase C(PKC)-δ activation in the pathogenesis of acute liver failure(ALF) in a well-characterized mouse model of D-galactosamine(D-Gal N)/lipopolysaccharide(LPS)-induced ALF.METHODS: BALB/c mice were randomly assigned to five groups, and ALF was induced in mice by intraperitoneal injection of D-Ga IN(600 mg/kg) and LPS(10 μg/kg). Kaplan-Meier method was used for survival analysis. Serum alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels at different time points within one week were determined using a multiparameteric analyzer. Serum levels of high-mobility group box 1(HMGB1), tumor necrosis factor(TNF)-α, interleukin(IL)-1β, IL-6, and IL-10 as well as nuclear factor(NF)-κB activity were determined by enzyme-linked immunosorbent assay. Hepatic morphological changes at 36 h after ALF induction were assessed by hematoxylin and eosin staining. Expression of PKC-δ in liver tissue and peripheral blood mononuclear cells(PBMCs) was analyzed by Western blot.RESULTS: The expression and activation of PKC-δ were up-regulated in liver tissue and PBMCs of mice with D-Gal N/LPS-induced ALF. Inhibition of PKC-δ activation with rottlerin significantly increased the survival rates and decreased serum ALT/AST levels at 6, 12 and 24 h compared with the control group(P < 0.001). Rottlerin treatment also significantly decreased serum levels of HMGB1 at 6, 12, and 24 h, TNF-α, IL-6 and IL-1 β at 12 h compared with the control group(P < 0.01). The inflammatory cell infiltration and necrosis in liver tissue were also decreased in the rottlerin treatment group. Furthermore, sphingosine kinase 1(Sph K1) dependent PKC-δ activation played an important role in promoting NF-κB activation and inflammatory cytokine production in ALF.CONCLUSION: Sph K1 dependent PKC-δ activation plays an important role in promoting NF-κB activation and inflammatory response in ALF, and inhibition of PKC-δ activation might be a potential therapeutic strategy for this disease. AIM: To investigate the role of protein kinase C (PKC) -δ activation in the pathogenesis of acute liver failure (ALF) in a well-characterized mouse model of D-galactosamine (D-Gal N) / lipopolysaccharide (LPS) ALF. METHODS: BALB / c mice were randomly assigned to five groups, and ALF was induced in mice by intraperitoneal injection of D-Ga IN (600 mg / kg) and LPS for survival analysis. Serum levels of high-mobility group box 1 (HMT1) and aspartate aminotransferase (AST) levels at different time points within one week were used using a multiparameteric analyzer. α, interleukin (IL) -1β, IL-6, and IL-10 as well as nuclear factor (NF) -κB activity were determined by enzyme-linked immunosorbent assay. Hepatic morphological changes at 36 h after ALF induction were assessed by Hematoxylin and eosin staining. Expression of PKC-δ in liver tissue and peripheral blood mononuclear cells (PBMC s) was analyzed by Western blot. RESULTS: The expression and activation of PKC-δ were up-regulated in liver tissue and PBMCs of mice with D-Gal N / LPS-induced ALF. Inhibition of PKC-δ activation with rottlerin increased increased the survival rates and decreased serum ALT / AST levels at 6, 12 and 24 h compared with the control group (P <0.001). Rottlerin treatment also significantly decreased serum levels of HMGB1 at 6, 12, and 24 h, TNF- IL-6 and IL-1 β at 12 h compared with the control group (P <0.01). The inflammatory cell infiltration and necrosis in liver tissue also also decreased in the rottlerin treatment group. Furthermore, sphingosine kinase 1 (Sph K1) dependent PKC-δ activation played an important role in promoting NF-κB activation and inflammatory cytokine production in ALF. CONCLUSION: Sph K1 dependent PKC-δ activation plays an important role in promoting NF-κB activation and inflammatory response in ALF, and inhibition of PKC -δ activation might be a potential th erapeutic strategy for this disease.