D-2HG Inhibits Glutamine Synthetase Activity and Induces Senescence in IDH-Mutant Gliomas

IDH1/2 mutations are prevalent genetic alterations in gliomas that facilitate metabolic reprogramming and epigenetic modifications, which are essential for glioma progression. However, their exact contributions to tumorigenesis remain to be fully elucidated. Cellular senescence is a known precursor to tumorigenesis, and multiple oncogenes can initiate this senescence program. Our study demonstrated that the IDH1 mutation inhibits the proliferation of astrocytes and glioma cells, inducing cellular senescence through mechanisms involving DNA damage and increased production of reactive oxygen species (ROS). Notably, these effects were mitigated by the addition of exogenous glutamine. Within cells, glutamine synthetase (GS) serves as the sole enzyme responsible for glutamine synthesis. We found that D-2-hydroxyglutarate (D-2HG), an oncometabolite generated by mutant IDH enzymes, directly inhibits GS activity by binding to the glutamate site, substantially reducing endogenous glutamine production and exacerbating senescence in IDH1-mutant glioma cells. Additionally, in human glioma samples, a greater prevalence of GS-positive astrocytes was detected in IDH-mutant gliomas, likely providing adequate glutamine to sustain growth and mitigate senescence in these cells. Our findings suggest that D-2HG promotes senescence in IDH1-mutant glioma cells by inhibiting GS activity and that disrupting glutamine transport between astrocytes and glioma cells may constitute a promising therapeutic strategy for targeting IDH-mutant gliomas.