Ma Anquan, Yang Ziqing, He Qixuan, Wang Wenhao, Ren Huiping, Zhai Chuanyao, Lan Jing
Department of Prosthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan 250012, China.
Department of Prosthodontics, Linyi People's Hospital, Shandong Second Medical University, Linyi, Shandong 276000, China.
Int J Biol Macromol. 2025 Jul 31:146486. doi: 10.1016/j.ijbiomac.2025.146486.
Environmental glyphosate exposure has been linked to glioblastoma (GBM), yet its molecular basis remains unclear. Integrating network-toxicology and druggable Mendelian randomization screens, we identified the Src-family kinase FYN as the principal glyphosate target. Molecular-dynamics simulations, surface-plasmon resonance (KD = 1.54 μM) and pull-down assays confirmed high-affinity binding and highlighted ASP353 as a dominant contact residue. Multi-omics profiling showed FYN over-expression and promoter hypomethylation in GBM, correlating with diminished immune infiltration. In U87 cells, sub-toxic glyphosate (0.1 mg/L, 12 h) up-regulated FYN, activated PI3K-AKT-mTOR signaling, increased GLUT1, LDHA and PKM2, and accelerated proliferation, migration and invasion; lentiviral sh-FYN reversed these effects and curtailed glycolytic flux. Orthotopic mouse studies mirrored the in-vitro findings, with FYN knock-down suppressing glyphosate-driven tumor growth. Exosomes derived from sh-FYN glioma cells weakened macrophage M2 polarization and reduced CXCL1, IL-10 and TGF-β secretion, revealing an immunometabolism axis. Collectively, these results establish FYN as the mechanistic conduit between glyphosate and GBM and demonstrate that targeting FYN-directly or via exosome delivery-reprograms tumor glycolysis and immunity, offering a tractable strategy against glyphosate-associated malignancy.
环境中接触草甘膦已被证明与胶质母细胞瘤（GBM）有关，但其分子基础仍不清楚。通过整合网络毒理学和可成药孟德尔随机化筛选，我们确定Src家族激酶FYN是草甘膦的主要靶点。分子动力学模拟、表面等离子体共振（KD = 1.54 μM）和下拉试验证实了高亲和力结合，并突出显示ASP353是主要的接触残基。多组学分析显示GBM中FYN过表达和启动子低甲基化，与免疫浸润减少相关。在U87细胞中，亚毒性草甘膦（0.1 mg/L，12小时）上调FYN，激活PI3K-AKT-mTOR信号通路，增加GLUT1、LDHA和PKM2，并加速增殖、迁移和侵袭；慢病毒sh-FYN逆转了这些作用并减少了糖酵解通量。原位小鼠研究反映了体外研究结果，FYN敲低抑制了草甘膦驱动的肿瘤生长。来自sh-FYN胶质瘤细胞的外泌体减弱了巨噬细胞M2极化并减少了CXCL1、IL-10和TGF-β分泌，揭示了一条免疫代谢轴。总体而言，这些结果确定FYN是草甘膦与GBM之间的机制传导途径，并表明靶向FYN——直接或通过外泌体递送——可重编程肿瘤糖酵解和免疫，为对抗草甘膦相关恶性肿瘤提供了一种可行的策略。
