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

Area of Science:

• Oncology
• Toxicology
• Molecular Biology

Background:

• Environmental glyphosate exposure is a suspected risk factor for glioblastoma (GBM).
• The precise molecular mechanisms linking glyphosate to GBM remain largely unknown.
• Understanding these links is crucial for developing effective cancer prevention and treatment strategies.

Purpose of the Study:

• To identify the molecular target of glyphosate relevant to glioblastoma.
• To elucidate the signaling pathways and cellular processes affected by glyphosate in GBM.
• To explore FYN kinase as a therapeutic target for glyphosate-induced GBM.

Main Methods:

• Network-toxicology and Mendelian randomization screens to identify glyphosate targets.
• Molecular-dynamics simulations, SPR, and pull-down assays to confirm FYN binding.
• Multi-omics profiling, cell-based assays (U87), and orthotopic mouse models to assess FYN's role in GBM.
• Exosome analysis to investigate immunometabolic effects.

Main Results:

• FYN (a Src-family kinase) was identified as the principal high-affinity glyphosate target.
• Glyphosate up-regulated FYN in GBM cells, activating PI3K-AKT-mTOR signaling and promoting tumor growth, migration, and invasion.
• FYN knockdown reversed glyphosate-induced effects and suppressed tumor growth in vivo.
• Targeting FYN modulated tumor glycolysis and reprogrammed the tumor immune microenvironment via exosomes.

Conclusions:

• FYN kinase is the mechanistic link between glyphosate exposure and glioblastoma development.
• Targeting FYN, directly or through exosome-mediated delivery, offers a promising therapeutic strategy for glyphosate-associated GBM.
• This research uncovers a novel immunometabolism axis in GBM driven by FYN signaling.