Gan-tang-yi decoction attenuates endoplasmic reticulum stress in cirrhotic rats and CCl4-induced BRL-3A cells by regulating PERK/ATF4/CHOP pathway

BACKGROUNDLiver cirrhosis, a leading cause of global mortality, is characterized by progressive hepatic dysfunction and limited treatment options.Endoplasmic reticulum (ER) stress, particularly the pro-apoptotic protein kinase RNA-like ER kinase (PERK)/activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) signaling axis, is implicated in chronic liver diseases.Gan-tang-yi decoction (GTYD) has been shown to have hepatoprotective effects, but its mechanism concerning ER stress in cirrhosis remains unclear. AIMTo investigate the effects of GTYD against cirrhosis and its underlying mechanism using an integrated research method. METHODSWe employed an integrated approach utilizing a carbon tetrachloride (CCl 4 )-induced insulin-resistant cirrhotic rat model and CCl 4 -injured BRL-3A hepatocytes.The rats were treated with GTYD, with or without the PERK-specific agonist CCT020312.In vitro, cells were treated with serum containing GTYD along with the ER stress inhibitor 4-phenyl butyrate or the ER stress inducer thapsigargin.The tests performed included proteomic analysis, histopathology, biochemical examination of liver function and apoptosis, and analysis of the proteins involved in the main pathway of ER stress. RESULTSGTYD administration significantly improved liver histology, metabolic parameters, and liver function in cirrhotic rats.These benefits were paralleled by a marked downregulation of the expression of PERK/ATF4/CHOP pathway components, including glucose-regulating protein 78, p-PERK, ATF4, and CHOP, and a reduction in hepatocellular apoptosis and fibrosis.More importantly, the combination of CCT020312 4 / 36 and GTYD reversed the effects of GTYD protection.Serum containing GTYD administered in vitro was also effective at promoting the survival of cells and inhibiting cytotoxicity and apoptosis in a dose-dependent manner, which inhibited the expression of the PERK/ATF4/CHOP cascade.GTYD was protective and was imitated by 4-phenyl butyrate and blocked by thapsigargin. CONCLUSIONOverall, our results show that GTYD has considerable hepatoprotective effects on cirrhosis, primarily through the suppression of ER stress-mediated apoptosis via the PERK/ATF4/CHOP signaling pathway.