目的 采用网络毒理学结合分子对接技术，探讨双酚A在代谢相关脂肪性肝病发病过程中的潜在分子靶点及其作用机制。方法 利用ProTox-3.0平台预估双酚A的毒性特征，通过ChEMBL、STITCH、SwissTargetPrediction数据库预测双酚A的潜在作用靶点，从GeneCards、OMIM、TTD数据库获取代谢相关脂肪性肝病相关靶点，取交集获得共同靶点。采用DAVID数据库进行基因本体（GO）功能注释和京都基因与基因组百科全书（KEGG）通路富集分析。利用STRING数据库构建蛋白质相互作用网络，借助Cytoscape软件的MCODE与cytoHubba插件筛选核心靶点。运用分子对接与分子动力学模拟技术评估双酚A与核心靶点的结合能力与复合物稳定性。结果 共获得双酚A相关靶点748个，代谢相关脂肪性肝病相关靶点1 994个，交集得到177个共同靶点。蛋白质相互作用（PPI）网络分析识别出以NADH脱氢酶[泛醌]铁硫蛋白2（NDUFS2）为核心的关键靶点。GO与KEGG分析提示，NDUFS2主要参与氧化磷酸化及能量代谢过程。分子对接结果表明，双酚A与NDUFS2的C5结合口袋可稳定结合，结合能为-7.3 kcal/mol。随后的100 ns分子动力学模拟表明，双酚A与NDUFS2复合物在动态环境下构象稳定，结合良好。结论 双酚A暴露可能通过直接作用于NDUFS2，干扰线粒体能量代谢过程，从而促进代谢相关脂肪性肝病的发生发展。

Objective To investigate the potential molecular targets and mechanisms of bisphenol A in the pathogenesis of metabolic associated fatty liver disease by using network toxicology combined with molecular docking. Methods The toxicological profile of BPA was initially assessed using the ProTox-3.0 online platform. Potential protein targets of bisphenol A were predicted through the ChEMBL, STITCH, and SwissTargetPrediction databases, while metabolic associated fatty liver disease-related targets were retrieved from GeneCards, OMIM, and TTD databases. Common targets were identified by intersecting the bisphenol A and metabolic associated fatty liver disease-related target sets. GO functional annotation and KEGG pathway enrichment analyses were performed on the common targets using the DAVID database. A protein-protein interaction network was constructed using the STRING database, and core targets were identified by applying the MCODE and cytoHubba plugins in Cytoscape. Molecular docking and molecular dynamics simulations were subsequently employed to evaluate the binding affinity and complex stability between bisphenol A and the core targets. Results A total of 748 bisphenol A-related targets, and 1 994 metabolic associated fatty liver disease-related targets were obtained, with 177 common targets identified. PPI network analysis revealed that NDUFS2 served as a core target. GO and KEGG analyses indicated that NDUFS2 is primarily involved in oxidative phosphorylation and energy metabolism. Molecular docking demonstrated that bisphenol A stably binds to the C5 pocket of NDUFS2 with a binding energy of -7.3 kcal/mol. Subsequent 100 ns molecular dynamics simulations demonstrated that the bisphenol A and NDUFS2 complex maintained conformational stability and favorable binding under dynamic conditions. Conclusion Bisphenol A exposure may directly target NDUFS2, disrupt mitochondrial energy metabolism, and thereby promote the development of metabolic associated fatty liver disease.

R99

中华中医药学会青年培英计划项目(202557-011)