Glioblastoma cells utilize evolutionarily adapted cell metabolism to promote their malignant proliferation.

Glioblastoma is the most aggressive primary brain tumor in adults, with limited therapeutic success and, therefore, poor prognosis. Its malignancy is partly driven by the high proliferative capacity of glioblastoma cells, yet the underlying molecular mechanisms remain unclear. Recent studies have revealed transcriptomic similarities between glioblastoma cells and human fetal neural stem/progenitor cells (NSCs), suggesting that glioblastoma may exploit developmental programs that promote NSC proliferation. Fetal human NSCs rely on glutaminolysis-a metabolic pathway induced by the human-specific mitochondrial protein ARHGAP11B-to sustain proliferation. Here, we show that ARHGAP11B expression correlates with glioma malignancy and is essential for glioblastoma cell proliferation, implicating a critical role of glutaminolysis in tumor growth. Among glutaminolysis-related enzymes, glutamic-oxaloacetic transaminase 2 (GOT2) shows a strong positive correlation with glioma grade and poor patient prognosis. Functional assays reveal that GOT2 knockdown significantly suppresses glioblastoma cell growth, indicating that GOT2-mediated glutaminolysis is critical for their proliferation. Metabolomic profiling further shows that GOT2 is required for nucleotide precursor synthesis, underscoring its role in supporting DNA replication. Consistently, GOT2 depletion reduces the proportion of glioblastoma cells in the S phase of the cell cycle. These findings suggest glioblastoma cells hijack an evolutionarily adapted metabolic program to support malignant growth.