Background and Aims The pathogenesis of sepsis-related liver injury (SRLI) remains unclear, and the inflammatory damage of bacterial lipopolysaccharides (LPS) to the hepatic endothelial cells may be an important process. Previous studies have suggested that RNA-specific adenosine deaminase 1 (ADAR1) may be involved in local and systemic inflammatory responses during endothelial stress through regulating the endothelial cell function-related protein Caveolin-1 (Cav-1). Therefore, this study was conducted as a preliminary assessment to analyze the roles of ADAR1 and Cav-1 in SRLI, so as to help find a new approach for early prevention and management of SRLI.Methods Mouse sepsis models were induced in 20 ADARl knockout mice (ADAR1^ECKO) and 20 wild-type mice (ADAR1^flox/flox) by injection of LPS (20 mg/kg). Ten mice in each group were sacrificed at 6 h after LPS injection, the liver tissues were harvested for histopathological observation by HE staining and the liver sinusoidal endothelial cells (LSECs) were isolated for observation of the expressions of Cav-1 and its downstream protein VE-cadherin by cellular immunofluorescence. The remaining mice in the two groups were used for survival observation. In LSECs from normal wild-type mice after ADARl siRNA transfection, the proliferative ability was determined by endothelial tube formation assay, and the expressions of the relevant downstream proteins of Cav-1 were determined by Western blot analysis.Results The results of survival observation showed that the time of death of ADAR1^ECKO mice was earlier than that of ADAR1^flox/flox mice, and the survival rate of ADAR1^ECKO mice was lower than that of ADAR1^flox/flox mice after LPS injection (both P<0.05); the results of histopathological showed that the liver injury in ADAR1^ECKO was severe than that in ADAR1^flox/flox mice at 6 h after LPS injection; the results of cellular immunofluorescence showed that the expressions of Cav-1 and VE-cadherin in LSECs were lower from ADAR1^ECKO mice than those from ADAR1^flox/flox mice. In LSECs from normal wild-type mice after ADARl siRNA transfection, the tube formation ability was decreased, and the expression of Cav-1 downstream protein VE-cadherin was down-regulated, while the expression of β-Catenin had no obvious change.Conclusion The down-regulation or functional deficiency ADAR1 can cause the aggravation of SRLI, and the mechanism is probably associated with its regulating the activity of the Cav-1/VE-cadherin pathway. Thus, activation of the ADAR1/Cav-1/VE-cadherin pathway is potentially an effective strategy for prevention and treatment of SRLI.