吡咯里西啶生物碱（PAs）是一类天然的肝毒性成分。许多中草药含有PAs但临床未见明显毒害，提示其潜在拮抗成分的存在。文献报道，氧化应激及其介导的线粒体凋亡或坏死是PAs诱导肝损伤的重要途径，而Nrf2在其中起着关键作用。我们前期研究发现，自噬受PAs诱导并与凋亡发生交互作用，而川紫菀多糖具有抗PAs肝毒性作用，其机制与减轻肝组织氧化应激有关。据此推测，Nrf2介导的ROS-自噬通路可能在川紫菀多糖的拮抗作用中发挥重要作用。本项目拟以此为切入点展开深入研究，采用分子生物学、代谢组学和基于机制的（药）毒代动力学与（药）毒效学相结合等方法，在分子、细胞及整体水平上剖析川紫菀多糖抗PAs肝毒性的作用机制及其结构基础；通过组分作用整体性分析，探讨多糖干预下PAs低剂量兴奋效应和组分间协同作用机制。通过研究揭示多糖在含PAs中草药临床应用中的重要性，同时为研究PAs解毒药物及发掘新药源提供理论基础。

Pyrrolizidine alkaloids (PAs) are a group of hepatotoxic ingredients found in many Chinese medicinal herbs (CMHs). Numerous clinical applications of PA-containing CMHs but without obvious toxic effects suggest that there may be some potential antagonists against PAs in the herbs. To date, the diverse metabolic and toxic mechanisms of PAs have been extensively studied, however, the therapeutically active compounds, especially those antagonistic ingredients of PA-induced hepatotoxicity in PA-containing CMHs are largely underappreciated. The published results have shown that oxidative stress followed by mitochondrial apoptosis or necrosis is an important pathway for PAs-induced liver injury, in which nuclear factor erythroid 2-related factor 2 (Nrf2) plays a central role. Our previous studies found that PAs could induce autophagy and its interaction with apoptosis, while Ligularia hodgsonii polysaccharides have anti-PAs hepatotoxicity effect through reducing oxidative stress in liver tissue. Accordingly, we hypothesize that polysaccharides may be a kind of important active substances in Ligularia hodgsonii against PA intoxication by interference with Nrf2-mediated reactive oxygen species (ROS)-autophagy signaling pathway. Based on this point, the key roles of polysaccharides in the regulation of PA-induced hepatotoxicity in Ligularia hodgsonii will be studied in depth. The underlying mechanism and structural basis of Ligularia hodgsonii polysaccharides for PA detoxification will be dissected at molecular, cellular and whole animal levels by means of molecular biology, metabolomics and the mechanism-based toxicokinetics in combination with toxicodynamics and pharmacokinetics with pharmacodynamics. Moreover, the potential hormesis of PAs under the intervention of polysaccharides and component-component synergistic effects will be explored according to the analyses of the holistic actions of multi-components. This study will be helpful for better understanding the important role of polysaccharides in ensuring quality, safety, and efficiency of the PA-containing CMHs in Chinese medical practice, and meanwhile, provide the scientific basis for further development of hepatoprotective agents as well as new medicinal resources against PA intoxication.