miR-15a-5p Regulates Ferroptosis in Glioblastoma by Targeting GLS2

Glioblastoma (GBM) remains the most lethal primary brain tumor, and the molecular mechanisms driving its aggressiveness are incompletely understood. Recent multi-omics analyses have identified miR-15a-5p as one of the core microRNAs most closely associated with GBM. This study aimed to investigate the functional role and mechanism of miR-15a-5p in GBM pathogenesis.

Expression of miR-15a-5p was analyzed in GBM tissues and cell lines. Genetic silencing experiments were performed to assess cell proliferation, migration, and tumor growth across multiple GBM cell lines and in an intracranial xenograft model. Ferroptosis-related changes were evaluated, and target validation was conducted using luciferase reporter assays. Rescue experiments were performed by co-modulating miR-15a-5p and GLS2.

miR-15a-5p was significantly overexpressed in GBM tissues and cell lines, and high expression correlated with poor patient survival. Genetic silencing of miR-15a-5p suppressed GBM cell proliferation and migration and inhibited tumor growth in vivo. Mechanistically, miR-15a-5p directly targeted the 3'UTR of glutaminase 2 (GLS2). Knockdown of miR-15a-5p induced ferroptosis-related features, including GPX4 downregulation, ACSL4 upregulation, iron accumulation, lipid peroxidation, and mitochondrial contraction. These effects were reversed by GLS2 knockdown in both in vitro and in vivo rescue experiments.

The miR-15a-5p/GLS2 axis represents a previously unrecognized mechanism by which GBM cells resist ferroptosis. These findings not only define a novel mechanism underlying ferroptosis regulation in GBM but also identify the miR-15a-5p/GLS2 axis as a potential entry point for ferroptosis-based therapeutic intervention. Targeting this axis may provide a rational strategy to modulate ferroptosis and suppress GBM progression.