Sufentanil Protects the Liver from Ischemia/Reperfusion-Induced Inflammation and Apoptosis by Inhibiting ATF4-Induced TP53BP2 Expression.

Liver ischemia-reperfusion (I/R) injury is a pathological process that often occurs during liver and trauma surgery. This study aimed to investigate the protective effect and potential mechanisms of sufentanil on hepatic I/R injury. I/R rat model and hypoxic/reoxygenation (H/R)-induced buffalo rat liver (BRL)-3A cell model were established. Following pretreatment with sufentanil, the enzymatic activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rat serum and the changes of hepatic histopathology were evaluated to track the extent of liver injury. The levels of inflammatory factors were determined with ELISA kits and RT-qPCR. The infiltration of macrophages was assessed after detecting monocyte chemoattractant protein 1 (MCP-1) and F4/80 expression. Additionally, apoptosis was measured by means of TUNEL staining, and gene expression related to apoptosis was examined using RT-qPCR and western blotting. Then, TP53BP2 was overexpressed in BRL-3A cells exposed to H/R condition to evaluate whether sufentanil defended the liver against injury by regulating TP53BP2 expression. Moreover, the potential binding site of ATF4 on the TP53BP2 promoter was analyzed using JASPAR databases and verified by chromosomal immunoprecipitation (ChIP) assay. Furthermore, TP53BP2 expression and endoplasmic reticulum stress (ERS)-related protein levels were determined after ATF4 was overexpressed in sufentanil-treated BRL-3A cells. Results revealed that sufentanil significantly improved hepatic I/R injury, decreased the levels of inflammatory factors, and alleviated hepatocyte apoptosis. Notably, upregulated TP53BP2 expression was observed in hepatic tissues, and TP53BP2 overexpression markedly reversed the protective effects of sufentanil on the inflammation and apoptosis in H/R-stimulated BRL-3A cells. Additionally, ATF4 was confirmed to combine with the TP53BP2 promoter. ATF4 upregulation attenuated the inhibitory effects of sufentanil on the expression of TP53BP2 and ERS-associated proteins. These findings demonstrated that sufentanil protects the liver from inflammation and apoptosis injury induced by I/R by inhibiting ATF4 expression and further suppressing TP53BP2 expression, suggesting a promising therapeutic candidate for the treatment of liver I/R injury.