Salvianolic Acid C Protects Against Hepatic Ischemia-Reperfusion Injury via Heat Shock Protein 90α-Mediated Activation of the Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling Pathway.

Abstract

Hepatic ischemia-reperfusion injury (HIRI) is a major challenge in liver surgery, and effective pharmacological interventions are lacking. Salvianolic acid C (SaC) has shown protective effects in various pathologies, but its role in HIRI remains unclear. This study investigated whether SaC protects against HIRI and elucidated the underlying mechanisms. Bioinformatics analysis of GSE151648 identified differentially expressed heat shock proteins (HSPs) and associated pathways. Molecular docking predicted SaC binding to HSP90α and AKT. A murine HIRI model was established with SaC (10 mg/kg, i.p.) pretreatment for 7 days. Histology, serum transaminases, and oxidative stress markers assessed liver injury. HSP90α inhibition used 17-AAG; in vitro hypoxia/reoxygenation (H/R) experiments used AML12 hepatocytes. Clinical validation used paired liver tissues from patients undergoing ex vivo liver resection and autotransplantation. Twenty-one HSP genes were differentially expressed, with HSP90α as a core hub gene in the PI3K/AKT pathway. SaC showed high binding affinity for HSP90α (-8.7 kcal/mol) and p-AKT1 (-10.9 kcal/mol). In mice, SaC upregulated HSP90α, reduced necrosis and serum transaminases, decreased MDA and increased GSH and SOD, suppressed TNF-α, IL-1β, and IL-6, and reduced apoptosis (Bax/Bcl-2, cleaved caspase-3), while activating PI3K/AKT. These effects were abolished by 17-AAG and confirmed in H/R-treated AML12 cells. HSP90α was also upregulated in post-transplant human livers. SaC protects against HIRI by upregulating HSP90α and activating PI3K/AKT, thereby alleviating oxidative stress, inflammation, apoptosis, and necrosis. These findings support SaC as a potential therapeutic strategy for HIRI.