Astragaloside IV Ameliorates Acetaminophen-Induced Liver Injury via Targeting the PCK1/PPARG/RXRA-Mediated PPAR...

Acetaminophen (APAP) overdose can induce hepatic injury and even acute liver failure. Astragaloside IV (AS-IV), a saponin isolated from Astragalus membranaceus, demonstrates protective effects on both digestive and immune systems owing to its antioxidant and anti-inflammatory properties. This study aims to investigate the protective effects and underlying mechanisms of AS-IV against APAP-induced liver injury (AILI) in mice. Potential therapeutic targets of AS-IV against AILI were predicted through network pharmacology and GEO data mining. Functional enrichment analysis was performed on the identified targets. Molecular docking and dynamics simulations were conducted to validate the binding interactions between AS-IV and core targets within the PPAR signaling pathway. For in vivo validation, fifty C57BL/6 mice were randomly allocated into five groups: control, APAP model, AS-IV low-dose, AS-IV high-dose, and N-acetylcysteine treatment groups. Following model establishment, serum AST and ALT levels were measured to assess liver function. Hepatic histopathological changes were evaluated by HE staining, while RT-qPCR and WB were employed to quantify the expression of key genes and proteins. Network pharmacology analysis identified 43 potential therapeutic targets of AS-IV against AILI, including key molecules such as IL1B, PPARG, RXRA, and FOS. KEGG pathway enrichment revealed significant associations with the PPAR signaling pathway, measles, and non-alcoholic fatty liver disease. In vivo experiments demonstrated that AS-IV treatment effectively attenuated histopathological liver damage in AILI mice, as evidenced by significantly reduced serum ALT and AST levels. Furthermore, AS-IV administration markedly upregulated both mRNA and protein expression levels of critical metabolic regulators PCK1, RXRA, and PPARG. In conclusion, AS-IV alleviates AILI by modulating the PPAR signaling pathway through regulation of PCK1, PPARG, and RXRA.