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Astragaloside IV (AS\u2010IV), a saponin isolated from Astragalus membranaceus, demonstrates protective effects on both digestive and immune systems owing to its antioxidant and anti\u2010inflammatory properties. This study aims to investigate the protective effects and underlying mechanisms of AS\u2010IV against APAP\u2010induced liver injury (AILI) in mice. Potential therapeutic targets of AS\u2010IV 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\u2010IV 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\u2010IV low\u2010dose, AS\u2010IV high\u2010dose, and N\u2010acetylcysteine 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\u2010qPCR and WB were employed to quantify the expression of key genes and proteins. Network pharmacology analysis identified 43 potential therapeutic targets of AS\u2010IV 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\u2010alcoholic fatty liver disease. In vivo experiments demonstrated that AS\u2010IV treatment effectively attenuated histopathological liver damage in AILI mice, as evidenced by significantly reduced serum ALT and AST levels. Furthermore, AS\u2010IV administration markedly upregulated both mRNA and protein expression levels of critical metabolic regulators PCK1, RXRA, and PPARG. In conclusion, AS\u2010IV alleviates AILI by modulating the PPAR signaling pathway through regulation of PCK1, PPARG, and RXRA.<\/jats:p>","DOI":"10.1002\/jbt.70942","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T07:05:22Z","timestamp":1780556722000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Astragaloside IV Ameliorates Acetaminophen\u2010Induced Liver Injury via Targeting the PCK1\/PPARG\/RXRA\u2010Mediated PPAR Signaling Pathway"],"prefix":"10.1002","volume":"40","author":[{"given":"Shunlei","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Spleen and Stomach Diseases Liyang Hospital of Chinese Medicine Changzhou Jiangsu China"},{"name":"The First Clinical Medical College Nanjing University of Chinese Medicine Nanjing Jiangsu 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