Wang Chenglin, Wang Xin, Deng Yaxing, Hu Yingchun, Hu Li
Department of Emergency Medicine, The Affiliated Hospital of Southwest Medical University, No. 25 Taiping Street, Jiangyang District, Luzhou, Sichuan, China.
School of Stomatology, Southwest Medical University, Luzhou, Sichuan, China.
Sci Rep. 2025 Jul 18;15(1):26068. doi: 10.1038/s41598-025-11720-5.
As one of the most toxic molecules in the fungal kingdom, amatoxin exhibit exceptional thermal stability and acid resistance. Once ingested, these compounds are rapidly absorbed and transported unimpeded to vital organs. They disrupt cellular metabolism by inhibiting nucleic acid and protein synthesis in target organs, ultimately causing hepatic and renal necrosis. Without prompt intervention, this molecular sabotage can progress to multiorgan failure and death. Early diagnosis combined with aggressive therapeutic measures is crucial for mitigating acute hepatic damage and significantly improving survival outcomes. This study aims to elucidate the molecular mechanisms underlying amatoxin-induced hepatic injury and establish a theoretical framework for targeted therapeutic interventions. Computational toxicology approaches utilizing ProTox-3.0 and ADMETlab 2.0 platforms were employed to characterize amatoxin's toxicological profile. Target prediction was performed through STITCH and SwissTargetPrediction databases, while liver injury-associated targets were identified from GeneCards, OMIM, and TTD repositories. The intersectional targets underwent systematic bioinformatics analysis, including protein-protein interaction (PPI) network construction, Gene Ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Molecular docking simulations were subsequently conducted to characterize three-dimensional binding conformations between amatoxin and core target proteins. Computational screening identified 11 potential amatoxin targets using STITCH and SwissTargetPrediction databases. Parallel interrogation of GeneCards, OMIM, and TTD repositories yielded 1,730 liver injury-related genes. Venn diagram analysis pinpointed SP1 and CNR1 as consensus molecular targets at the amatoxin-hepatic injury interface. PPI network topology revealed critical nodal connections, while functional enrichment analyses delineated key biological processes and signaling pathways associated with these targets. Molecular docking simulations demonstrated high-affinity binding between amatoxin and both SP1 and CNR1, suggesting direct mechanistic interactions. Amatoxin likely exerts hepatotoxic effects through direct binding to the core molecular targets SP1 and CNR1, thereby perturbing downstream transcriptional regulation and disrupting critical signaling cascades, ultimately culminating in hepatic necrosis.
作为真菌界毒性最强的分子之一，鹅膏毒素具有出色的热稳定性和耐酸性。一旦摄入，这些化合物会迅速被吸收并畅通无阻地运输到重要器官。它们通过抑制靶器官中的核酸和蛋白质合成来扰乱细胞代谢，最终导致肝坏死和肾坏死。如果不及时干预，这种分子破坏会发展为多器官功能衰竭并导致死亡。早期诊断与积极的治疗措施相结合对于减轻急性肝损伤和显著改善生存结果至关重要。本研究旨在阐明鹅膏毒素诱导肝损伤的分子机制，并建立靶向治疗干预的理论框架。利用ProTox-3.0和ADMETlab 2.0平台的计算毒理学方法来表征鹅膏毒素的毒理学特征。通过STITCH和SwissTargetPrediction数据库进行靶点预测，同时从GeneCards、OMIM和TTD数据库中识别肝损伤相关靶点。对交集靶点进行系统的生物信息学分析，包括蛋白质-蛋白质相互作用（PPI）网络构建、基因本体（GO）注释和京都基因与基因组百科全书（KEGG）通路富集分析。随后进行分子对接模拟，以表征鹅膏毒素与核心靶蛋白之间的三维结合构象。通过计算筛选，利用STITCH和SwissTargetPrediction数据库确定了11个潜在的鹅膏毒素靶点。对GeneCards、OMIM和TTD数据库的并行查询产生了1730个肝损伤相关基因。维恩图分析确定SP1和CNR1是鹅膏毒素-肝损伤界面的共同分子靶点。PPI网络拓扑结构揭示了关键的节点连接，而功能富集分析描绘了与这些靶点相关的关键生物学过程和信号通路。分子对接模拟表明鹅膏毒素与SP1和CNR1均具有高亲和力结合，表明存在直接的机制相互作用。鹅膏毒素可能通过直接结合核心分子靶点SP1和CNR1发挥肝毒性作用，从而扰乱下游转录调控并破坏关键信号级联反应，最终导致肝坏死。
