Glyphosate targets FYN to regulate glycolysis and promote glioblastoma proliferation: A network toxicology study

作者：Anquan Ma, Ziqing Yang, Qi He, Wenhao Wang, Huiping Ren, Chuanyao Zhai, Jing Lan · 发表于：International Journal of Biological Macromolecules · 年份：2025 · DOI：10.1016/j.ijbiomac.2025.146486 · 被引用次数：4 · 研究领域：Epigenetics and DNA Methylation、Acute Myeloid Leukemia Research、Myeloproliferative Neoplasms: Diagnosis and Treatment

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.