Zheng Qiu, Peng Qingping, Shen Jianlin, Liu Huan
Department of Orthopedics, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, 646000, China.
Collage of Integrated Traditional Chines and Western Medicine, Southwest Medical University, Luzhou, Sichuan, 646000, China.
Toxicology. 2025 Jan;510:154009. doi: 10.1016/j.tox.2024.154009. Epub 2024 Nov 22.
The aim of this study was to apply a network toxicology strategy to investigate the potential toxicity and the molecular mechanisms underlying the aging-induced toxicity of acetyl tributyl citrate (ATBC). Utilizing the ChEMBL, SwissTargetPrediction, and CellAge databases, we identified 32 potential targets associated with ATBC exposure and aging. Subsequent optimization by STRING and Cytoscape software highlighted 11 core targets, including EGFR, STAT3, and BCL-2. A comprehensive analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways revealed that core targets of ATBC-induced senescence were predominantly enriched in pathways related to the positive regulation of cell proliferation, telomere shortening, cancer, and cellular senescence. Among these pathways, we selected four core genes of the cellular senescence pathway (MAPK14, CDK2, MDM2, and PIK3CA) for molecular docking with Autodock, which confirmed the high binding affinity between ATBC and the core targets. In conclusion, these findings indicate that ATBC may contribute to human aging by modulating the positive regulation of cell proliferation, the telomere shortening pathway, the cancer-related pathway, and the cellular senescence pathway. This study establishes a theoretical basis for exploring the molecular mechanisms of human aging induced by ATBC, alongside a systematic and effective framework for researchers to assess the potential toxicity of various chemical products.
本研究的目的是应用网络毒理学策略，以研究柠檬酸乙酰三丁酯（ATBC）的潜在毒性以及衰老诱导毒性背后的分子机制。利用ChEMBL、SwissTargetPrediction和CellAge数据库，我们鉴定了32个与ATBC暴露和衰老相关的潜在靶点。随后通过STRING和Cytoscape软件进行优化，突出了11个核心靶点，包括表皮生长因子受体（EGFR）、信号转导和转录激活因子3（STAT3）以及B淋巴细胞瘤-2（BCL-2）。对基因本体论（GO）和京都基因与基因组百科全书（KEGG）通路的综合分析表明，ATBC诱导衰老的核心靶点主要富集在与细胞增殖的正调控、端粒缩短、癌症和细胞衰老相关的通路中。在这些通路中，我们选择了细胞衰老通路的四个核心基因（丝裂原活化蛋白激酶14（MAPK14）、细胞周期蛋白依赖性激酶2（CDK2）、小鼠双微体2（MDM2）和磷脂酰肌醇-3激酶催化亚基α（PIK3CA））用于与Autodock进行分子对接，这证实了ATBC与核心靶点之间具有高结合亲和力。总之，这些发现表明，ATBC可能通过调节细胞增殖的正调控、端粒缩短通路、癌症相关通路和细胞衰老通路来促进人类衰老。本研究为探索ATBC诱导人类衰老的分子机制奠定了理论基础，同时为研究人员评估各种化学产品的潜在毒性建立了一个系统有效的框架。
