He Qiwang, Chen Yining, Huang Caiyun, Cong Xiaoqian, Li Yanan, Xiao Die, Ding Yanbing, Wan Bijiang
Hubei University of Chinese Medicine, Wuhan, 430061, China.
Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430061, China.
Sci Rep. 2025 Aug 11;15(1):29363. doi: 10.1038/s41598-025-11178-5.
The toxic side effects of acetyl tributyl citrate (ATBC) on humans are concerning, but studies related to its effects on osteoarthritis (OA) are lacking. Therefore, this study aimed to explore the potential targets and mechanisms of action of ATBC in OA through network toxicology. We obtained ATBC-related targets from the ChEMBL, Swiss Target Prediction, and STITCH databases and OA-related targets from the GeneCards, DisGeNET, and OMIM databases and identified overlapping targets. Core targets (key molecules in the progression of diseases) were determined via the STRING database and Cytoscape software, followed by further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to determine potential mechanisms in depth. Moreover, a gene interaction and competing endogenous RNA (ceRNA) network for the core targets was constructed. Additionally, the expression levels of the core targets were preliminarily validated using single-cell data from the GEO database. Furthermore, in-depth validation of the core targets was carried out through molecular docking and molecular dynamics simulations. A total of 132 overlapping targets between ATBC and OA were identified, and six core targets (TP53, EZH2, HDAC1, HDAC2, SIRT1, and SMARCA4) were further screened. The results of the enrichment analysis revealed that the core pathways related to the effect of ATBC on OA mainly involved key signaling cascades, including the thyroid hormone signaling pathway, the Notch signaling pathway, and cellular senescence. Single-cell analysis revealed that the core target is expressed in different cell subpopulations. Molecular docking and molecular dynamics simulation results indicate that there is a stable binding interaction between ATBC and the core target. This study provides a theoretical foundation for the molecular mechanisms of OA triggered by ATBC, highlighting the value of network toxicology in assessing the toxicity of emerging environmental pollutants. However, further clinical and experimental investigations are needed to validate these findings.
乙酰柠檬酸三丁酯（ATBC）对人体的毒副作用令人担忧，但关于其对骨关节炎（OA）影响的研究却很缺乏。因此，本研究旨在通过网络毒理学探索ATBC在OA中的潜在靶点和作用机制。我们从ChEMBL、瑞士靶点预测数据库和STITCH数据库中获取了与ATBC相关的靶点，并从GeneCards、DisGeNET和OMIM数据库中获取了与OA相关的靶点，然后确定了重叠靶点。通过STRING数据库和Cytoscape软件确定核心靶点（疾病进展中的关键分子），随后进行进一步的基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析，以深入确定潜在机制。此外，构建了核心靶点的基因相互作用和竞争性内源性RNA（ceRNA）网络。此外，利用来自GEO数据库的单细胞数据初步验证了核心靶点的表达水平。此外，通过分子对接和分子动力学模拟对核心靶点进行了深入验证。共鉴定出ATBC与OA之间的132个重叠靶点，并进一步筛选出6个核心靶点（TP53、EZH2、HDAC1、HDAC2、SIRT1和SMARCA4）。富集分析结果表明，ATBC对OA作用的核心途径主要涉及关键信号级联反应，包括甲状腺激素信号通路、Notch信号通路和细胞衰老。单细胞分析表明，核心靶点在不同细胞亚群中表达。分子对接和分子动力学模拟结果表明，ATBC与核心靶点之间存在稳定的结合相互作用。本研究为ATBC引发OA的分子机制提供了理论基础，突出了网络毒理学在评估新兴环境污染物毒性方面的价值。然而，需要进一步的临床和实验研究来验证这些发现。
