农用杀虫剂高效氯氟氰菊酯诱发肺癌的分子机制

Molecular mechanisms of lung cancer induced by the insecticide lambda-cyhalothrin

摘要:

农用杀虫剂高效氯氟氰菊酯(lambda-cyhalothrin, LCT)的不规范使用可导致残留，危及食品安全和人体健康。呼吸暴露是人体接触LCT的主要方式之一，然而LCT对呼吸系统的损伤效应尚不明晰。鉴于肺癌是重要的呼吸系统恶性肿瘤，阐明LCT暴露与肺癌发生的潜在关系及机制具有重要价值。本研究旨在运用生物信息学方法筛选并解析LCT影响肺癌发生的关键靶分子及其作用机制。首先利用网络毒理学方法确定LCT诱导肺癌发生的潜在核心靶点，随后通过功能注释探究LCT诱发肺癌相关的细胞通路，最后使用分子对接模拟LCT与共有核心靶点的结合模式。本研究筛选到LCT诱导大细胞肺癌发生的核心靶点50个，小细胞肺癌发生的核心靶点54个，肺鳞癌发生的核心靶点29个，肺腺癌发生的核心靶点28个。其中，EGFR、HSP90AA1、JUN、CCL2、MYC、CXCL8和HSPA4是4种肺癌亚型共有核心靶点。功能注释结果表明，LCT诱发肺癌发生的细胞通路主要包括泛素化修饰、趋化作用和肿瘤免疫。分子对接模拟结果显示，LCT与核心靶点可自发结合，氢键或π-cation是LCT与共有核心靶点结合的作用力。本研究可为高效氯氟氰菊酯诱发肺癌和呼吸系统损伤的风险评估提供理论依据。

Abstract:

The inappropriate utilisation of the agricultural insecticide lambda-cyhalothrin (LCT) has the potential to result in residues that compromise food safety and human health. Respiratory exposure represents a major route of LCT contact in humans. Nevertheless, its deleterious effects on the respiratory system remain inadequately characterized. It is imperative to elucidate the potential relationship and mechanisms by which lung cancer, a significant malignant neoplasm of the respiratory system, is associated with exposure to LCT. The objective of this study is to utilise bioinformatics methodologies to screen and analyse the key target molecules affected by LCT in the occurrence of lung cancer, and their mechanisms of action. Specifically, network toxicology methods were employed to identify core targets of LCT-induced lung cancer. Subsequently, functional annotation to delineate associated cellular pathways, and finally, molecular docking to simulate binding modes between LCT and shared core targets. Core target screening identified 50 targets for large cell lung cancer, 54 for small cell lung cancer, 29 for lung squamous cell carcinoma, and 28 for lung adenocarcinoma, with EGFR, HSP90AA1, JUN, CCL2, MYC, CXCL8, and HSPA4 shared in all subtypes. Functional annotation revealed that LCT-triggered oncogenic pathways predominantly involved ubiquitination, chemotaxis, and tumor immune signaling. Molecular docking demonstrated spontaneous binding of LCT to core targets mediated by hydrogen bonds and π-cation interactions. These results establish a theoretical framework for evaluating LCT-associated risks of lung cancer and respiratory system damage.