Cellular Metabolomics Reveals Hepatoprotective Mechanisms of Platycoside Metabolites Against Acetaminophen-Induced Liver Injury

  • Chem Biodivers. 2026 Apr;23(4):e02806. doi: 10.1002/cbdv.202502806.
Yu Peng  1  2 ,  Yuanhan Zhong  1  2 ,  Xiwa Wu  1  2 ,  Liyun Wen  1  2 ,  Guangpeng Liu  1  2 ,  Shouwen Zhang  1  2 ,  Bingbing Xu  3 ,  Yonghong Liang  1  2 ,  Huiliang Huang  1  2 ,  Junwei He  1  2 ,  Yong Feng  1  4 ,  Jinxiang Zeng  1  2 ,  Jian Liang  1  2
Affiliations
  • 1. Research Center for Traditional Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang, China.
  • 2. Jiangxi Key Laboratory For Sustainable Utilization of Chinese Material Medical Resources, Nanchang, China.
  • 3. Jiangxi Provincial Institute of Traditional Chinese Medicine, Nanchang, China.
  • 4. Library of Jiangxi University of Traditional Chinese Medicine, Nanchang, China.
PMID: 41983307 DOI: 10.1002/cbdv.202502806
Abstract

Elucidating mechanisms of natural product metabolites is key to safer, more effective drugs against drug-induced liver injury (DILI). This study used cellular metabolomics to investigate hepatoprotective effects of three structurally similar platycoside metabolites-platycodigenin (PDN), 3-O-β-D-glucopyranosyl platycodigenin (OPDN), and polygalacic acid (POLA)-against APAP-induced liver injury. Using AML-12 hepatocytes challenged with APAP, intracellular metabolites were profiled by UHPLC-LTQ-Orbitrap mass spectrometry (ESI+ and ESI-), followed by PCA/OPLS-DA to identify differential metabolites and MetaboAnalyst-based 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-component herbal paradigms, and providing a metabolomic foundation for optimized platycoside-derived DILI therapeutics.

Keywords
acetaminophen‐induced liver injury; cell metabolomics; hepatoprotection; platycosides metabolites; structure‐mechanism relationship.
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