Objective To investigate the effects and underlying molecular mechanisms of glycyrrhetinic acid (GLG) and glycyrrhizic acid (GLA) on alleviation of cisplatin (CP)-induced acute liver injury (ALI) based on proteomics. Methods A total of 50 SPF male Wistar rats were randomly divided into control group, model group, amifostine (200 mg/kg) group, GLG (100 mg/kg) group and GLA (200 mg/kg) group. Rats in GLG group and GLA group were given intragastric administration for eight consecutive days. Rats in amifostine group was given intraperitoneal administration from the 5th to the 8th day of the experiment, control group and model group were given intragastric administration of physiological saline. On the 5th day of the experiment, except for the control group, all other rats were induced to ALI with a single dose of cisplatin solution (8 mg/kg) via ip. Liver index, liver function and pathological changes in liver tissue were detected. Label free non-standard quantitative proteomics technology was used to analyze protein expressions in liver tissue, differentially expressed proteins were screen, and bioinformatics analysis was performed. The protein-protein interaction (PPI) integration network of drug and disease prediction intersection targets and differentially expressed proteins was constructed by integrating network pharmacology methods. The core targets were screened by cytoNCA, MCODE and cytoHubba, gene ontology (GO) function and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed. Key target expressions were validated using Western blotting, immunohistochemistry and other techniques. Results Compared with model group, the liver index and activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum of rats in GLG group and GLA group were significantly reduced (P < 0.05, 0.01, 0.001), and the pathological damage of liver tissue was significantly improved. Proteomic identification identified 23 potential key differentially expressed proteins each in cisplatin-induced ALI treated with GLG and GLA, enriched in multiple biological processes related to redox reactions, inflammation and apoptosis. PPI integrated network showed that signal transducer and activator of transcription 3 (STAT3), heme oxygenase 1 (HMOX1), protein kinase B1 (AKT1), B-cell lymphoma-2 (Bcl-2), cysteine aspartate protease-3 (Caspase-3) and tumor protein p53 (TP53) were key targets of GLG action network, HMOX1, Bcl-2, epidermal growth factor receptor (EGFR) and TP53 were key targets of GLA action network, and they can be enriched in phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway, tumor necrosis factor-α (TNF-α) signaling pathway, interleukin-17 (IL-17) signaling pathway, p53 signaling pathway, etc. The validation results showed that both GLG and GLA could significantly upregulate the p-Akt/Akt value and Bcl-2, superoxide dismutase (SOD) levels in liver tissue of ALI rats (P < 0.01, 0.001), and downregulate the expressions of Akt, HMOX1, STAT3, high mobility group box 1 protein (HMGB1) and levels of TNF-α, IL-1β, malondialdehyde (MDA) in liver tissue (P < 0.05, 0.01, 0.001). Conclusion GLG and GLA could effectively alleviate cisplatin-induced ALI, and their protective effects may be closely related to regulating Akt/STAT3/HMOX1 signaling axis, thereby inhibiting liver oxidative damage, cell apoptosis and inflammatory response.

acute liver injury  /  cisplatin  /  glycyrrhetinic acid  /  glycyrrhizic acid  /  proteomics  /  Akt/STAT3/HMOX1 pathway