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PubMed · 42641898

Phytolacca acinosa Roxb. induces intestinal toxicity through the histamine-MLCK-tight junction axis: Integrated evidence from proteomics, metabolomics, intestinal organoids and epithelial barrier validation.

Yucheng Qi·Xiaoyu Lin·Yangyi Huang·Kou Zhang·Jie Cao·Xiangyue Kong·Xiaobing Cui·Xingde Zhang·Xinzhi Wang·Hao Wu·Hongli Yu
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Abstract

Phytolacca acinosa Roxb. (PR) is a saponin-rich medicinal plant associated with gastrointestinal toxicity, but the mechanisms underlying PR-induced intestinal barrier injury remain unclear. In this study, raw PR extract was analytically characterized by UPLC-ZenoTOF-MS/MS, confirming triterpenoid saponins as the predominant constituents. C57BL/6 J mice were orally exposed to characterized PR extract (1.20 or 12.0 g/kg for 5 h), and Caco-2 cells and mouse intestinal organoids were used to assess epithelial toxicity and barrier disruption. Histopathology, ELISA, FITC-dextran permeability assays, immunofluorescence, CCK-8, LDH release, western blotting, DIA-based proteomics and untargeted metabolomics were integrated to define toxicological mechanisms. PR induced dose-dependent intestinal inflammation and barrier dysfunction, with the ileum as the most sensitive target. PR increased serum DAO and D-lactate and intestinal TNF-α and IL-1β, disrupted organoid morphology, enhanced epithelial permeability, and reduced ZO-1 expression. Proteomics revealed changes in inflammatory, lipid-metabolic, cytoskeletal and tight-junction pathways, including upregulation of MLCK3 and phospholipase-related proteins and downregulation of ZO-1 and ZO-2. Metabolomics identified histidine metabolism disturbance and histamine accumulation. Integrated multi-omics and pharmacological validation indicated that histamine activated the PLC/IP₃/Ca²⁺/CaM/MLCK cascade, promoting MLC phosphorylation, tight-junction disassembly and epithelial leakiness. MLCK inhibition partially restored ZO-1/ZO-2 expression and attenuated PR-induced epithelial injury. These findings identify the histamine-MLCK-tight junction axis as a key mechanism of PR-induced intestinal toxicity and support hazard identification of saponin-rich PR exposure.

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AnimalsTight JunctionsIntestinal Barrier FunctionProteomicsCaco-2 CellsHumansMice, Inbred C57BLHistamineMetabolomicsPlant ExtractsMyosin-Light-Chain KinaseIntestinal MucosaMiceMaleTandem Mass SpectrometryHistamine–MLCK axisIntestinal toxicityMongolian medicinePhytolacca acinose Roxb.Proteomics and metabolomicsTight junctionJournal Article

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Yucheng Qi, Xiaoyu Lin, Yangyi Huang, Kou Zhang, Jie Cao, Xiangyue Kong, Xiaobing Cui, Xingde Zhang, Xinzhi Wang, Hao Wu, Hongli Yu. 2026-08-25. Phytolacca acinosa Roxb. induces intestinal toxicity through the histamine-MLCK-tight junction axis: Integrated evidence from proteomics, metabolomics, intestinal organoids and epithelial barrier validation.. https://doi.org/10.1016/j.toxlet.2026.113181

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Journal Article resourceAnimals subjectHumans subjectJournal Article subjectMale subjectMetabolomics subjectMice subjectPlant Extracts subject

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