Exploring the components of hepatotoxicity induced by Senecio scandens Buch.-Ham. based on integrated network toxicology, metabolomics, and in vivo experiments.

IF 1.5 4区医学 Q4 PHARMACOLOGY & PHARMACY

Xenobiotica Pub Date : 2026-05-01 Epub Date: 2026-05-14 DOI:10.1080/00498254.2026.2668400

Shunjun Yang, Hongxin Wang, Bowen Gong, Rong Tan, Ying Liu, Tiantai Wu, Yunfang Jiang, Qing Rao, Weiwei Li, Jia Yu, Chang Lin, Yang Jin, Shiyu Zhang

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引用次数: 0

Abstract

Background: 1. Senecio scandens Buch.-Ham. (SBH) is widely used in traditional Chinese medicine, yet its clinical application is constrained by hepatotoxic pyrrolizidine alkaloids (PAs). The relative toxic contributions of individual PAs in SBH and their in vivo metabolic consequences remain unclear.

Purpose: 2. This study sought to elucidate PAs-related hepatotoxicity of SBH by integrating network toxicology, LC-MS/MS fingerprinting, in vivo toxicity evaluation, and liver metabolomics.

Methods: 3. Network toxicology and molecular docking were used to prioritise hepatotoxic PAs and their putative targets. LC-MS/MS fingerprints of major PAs in 12 SBH samples were established. Spectrum-toxicity correlation analysis and untargeted metabolomics were used to assess hepatotoxicity-related associations and SPL-induced metabolic perturbations.

Results: 4. SPL, senecionine, adonifoline, and senkirkine were prioritised as candidate hepatotoxic PAs, with CYP3A4/CYP2C9 and DNA adduct-related pathways highlighted as potentially relevant toxicological nodes. Considerable regional variation in PAs levels was observed across SBH samples. Acute SBH exposure caused marked liver injury, and spectrum-toxicity modelling indicated that SPL showed the strongest association with hepatotoxicity among the detected PAs. Metabolomic profiling further showed that SPL exposure was associated with alterations in lipid and bile acid metabolism, glutathione metabolism, and the pentose phosphate pathway, together with enrichment of xenobiotic metabolism by cytochrome P450 and chemical carcinogenesis-DNA adduct pathways.

Conclusion: 5. SPL is closely associated with SBH-induced hepatotoxicity and produces a metabolic signature consistent with canonical PAs bioactivation. Although SPL appears to be the most influential PAs among those detected, definitive comparisons of toxic potency require further validation using equimolar pure-compound exposure models.

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山参草肝毒性成分的探讨。基于综合网络毒理学，代谢组学和体内实验。

背景：Senecio scandens buchh .- ham。（SBH）在中药中应用广泛，但其临床应用受到肝毒性吡咯利西啶生物碱（PAs）的限制。复杂SBH基质中单个PAs的相对毒性贡献及其体内代谢后果仍不清楚。目的：本研究旨在通过网络毒理学、LC-MS/MS指纹图谱、体内毒性评估和肝脏代谢组学等手段，阐明与pas相关的SBH肝毒性。方法：采用网络毒理学和分子对接的方法对肝毒性pa及其可能的靶点进行排序。采用LC-MS/MS指纹图谱建立了来自12个地区的SBH主要PAs的指纹图谱。采用灰色关联分析和ops回归相结合的光谱-毒性关联模型来评估PAs丰度与小鼠肝毒性之间的关系。非靶向代谢组学进一步描述了senechiphylline （SPL）引起的肝脏代谢紊乱。结果：SPL、senkirkine、adonifoline和senkirkine被优先考虑为候选肝毒性PAs， CYP3A4/CYP2C9和DNA加合物相关途径被强调为潜在的相关毒理学节点。在SBH样本中观察到相当大的区域差异。急性SBH暴露引起明显的肝损伤，光谱毒性模型显示SPL与肝毒性的相关性最强。代谢组学分析进一步表明，SPL暴露与脂质和胆汁酸代谢、谷胱甘肽代谢和戊糖磷酸途径的实质性改变有关，还与细胞色素P450和化学致癌- dna加合物途径的外源代谢富集有关。结论：SPL与sbh诱导的肝毒性密切相关，并产生与典型PAs生物激活一致的代谢特征。虽然SPL似乎是检测到的最具影响力的pa，但毒性效力的明确比较需要使用等摩尔纯化合物暴露模型进一步验证。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Xenobiotica 医学-毒理学

CiteScore

3.80

自引率

5.60%

发文量

审稿时长

2 months

期刊介绍： Xenobiotica covers seven main areas, including:General Xenobiochemistry, including in vitro studies concerned with the metabolism, disposition and excretion of drugs, and other xenobiotics, as well as the structure, function and regulation of associated enzymesClinical Pharmacokinetics and Metabolism, covering the pharmacokinetics and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in manAnimal Pharmacokinetics and Metabolism, covering the pharmacokinetics, and absorption, distribution, metabolism and excretion of drugs and other xenobiotics in animalsPharmacogenetics, defined as the identification and functional characterisation of polymorphic genes that encode xenobiotic metabolising enzymes and transporters that may result in altered enzymatic, cellular and clinical responses to xenobioticsMolecular Toxicology, concerning the mechanisms of toxicity and the study of toxicology of xenobiotics at the molecular levelXenobiotic Transporters, concerned with all aspects of the carrier proteins involved in the movement of xenobiotics into and out of cells, and their impact on pharmacokinetic behaviour in animals and manTopics in Xenobiochemistry, in the form of reviews and commentaries are primarily intended to be a critical analysis of the issue, wherein the author offers opinions on the relevance of data or of a particular experimental approach or methodology