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This study used cellular metabolomics to investigate hepatoprotective effects of three structurally similar platycoside metabolites\u2014platycodigenin (PDN), 3\u2010O\u2010\u03b2\u2010D\u2010glucopyranosyl platycodigenin (OPDN), and polygalacic acid (POLA)\u2014against APAP\u2010induced liver injury. Using AML\u201012 hepatocytes challenged with APAP, intracellular metabolites were profiled by UHPLC\u2013LTQ\u2010Orbitrap mass spectrometry (ESI+ and ESI\u2212), followed by PCA\/OPLS\u2010DA to identify differential metabolites and MetaboAnalyst\u2010based pathway enrichment. All three converged on core pathways: glycerophospholipid, purine, and amino sugar\/nucleotide sugar metabolism, preserving membrane integrity, mitigating oxidative stress, and modulating inflammation. Unique actions emerged: PDN\/OPDN targeted sphingolipid metabolism (apoptosis regulation); OPDN\/POLA enhanced glutathione and nicotinamide pathways (antioxidant defenses); OPDN exclusively regulated arachidonic acid metabolism (inflammation\/immune function); POLA uniquely modulated thiamine and pentose phosphate pathways (redox\/energy homeostasis). These findings highlight structural tailoring's role in diversifying mechanisms, supporting multi\u2010component herbal paradigms, and providing a metabolomic foundation for optimized platycoside\u2010derived DILI therapeutics.<\/jats:p>","DOI":"10.1002\/cbdv.202502806","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T09:02:18Z","timestamp":1776243738000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cellular Metabolomics Reveals Hepatoprotective Mechanisms of Platycoside Metabolites Against Acetaminophen\u2010Induced Liver Injury"],"prefix":"10.1002","volume":"23","author":[{"given":"Yu","family":"Peng","sequence":"first","affiliation":[{"name":"Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine Jiangxi University of Chinese Medicine  Nanchang China"},{"name":"Jiangxi Key Laboratory For Sustainable Utilization of Chinese Material Medical 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