Glutamine deprivation elevates EFNB3 and its potential link to macropinocytosis in glioblastoma

Glioblastoma (GBM) is the most common malignant brain tumor with a poor prognosis and prominent therapeutic resistance. l-glutamine (Gln) is crucial for cancer cell survival, and the microenvironment of GBM is often accompanied by Gln deficiency. To explore the molecular mechanisms by which GBM adapts to Gln deprivation, we performed proteomic profiling of clinical GBM tissues and established a Gln-deprived cell model. Our results showed that EFNB3 was significantly upregulated under Gln deprivation. Our data suggest a potential association between EFNB3 and Rac1-GTP, which may contribute to macropinocytosis through the Cdc42/PAK1 related signaling pathway. Knockdown of EFNB3 suppressed proliferation and macropinocytosis in GBM cells. Notably, the p38 MAPK pathway may correlate with sustained Rac1-GTP abundance and macropinocytosis, whereas blocking p38 MAPK signaling appears to attenuate Rac1-GTP levels and impair macropinocytosis without affecting EFNB3 expression. Collectively, our findings reveal a potential regulatory network involving the p38 MAPK/Rac1-GTP axis linked to EFNB3, indicating that EFNB3 may act as an important modulator of metabolic adaptation in GBM.