BACKGROUND: Glioblastoma (GBM) is the most malignant primary intracranial tumor. Owing to its unfavorable prognosis and frequent recurrence, patient outcomes are poor even with standard treatment. Recent studies have reported that FTY720, a structurally modified sphingosine extracted from Cordyceps sinensis, has preclinical antitumor efficacy and can regulate the microenvironment of GBM. However, the mechanism and effective utilization of FTY720, i.e., avoiding adverse reactions during systemic application in GBM remain unclear. PURPOSE: This study aimed to investigate the mechanisms by which FTY720 suppresses GBM growth and to explore the ability of a novel liposomal nanoparticle carrying FTY720 to directly target GBM. METHODS: Molecular, cytological, and histological techniques were employed to assess the effects of FTY720 on GBM cells, both in vitro and in vivo. Ferroptosis induction and its regulatory mechanisms were explored using a combination of reactive oxygen species (ROS), malondialdehyde (MDA) and glutathione (GSH) assays; transmission electron microscopy (TEM); and orthotopic GBM mouse model experiments. A nanoparticle drug delivery system based on liposomes (GF2-FTY720-LPs) was synthesized by thin film dispersion. RESULTS: Our study revealed that FTY720 induces ferroptosis in GBM cells through the AMPK-mTOR-GPX4 pathway, and that ginsenoside F2 (GF2) plays a synergistic role by reducing GSH levels. GF2-FTY720-LPs show superior targeting ability and potent inhibition of GBM in vivo, penetrating the blood-brain barrier and overcoming the shortcomings of systemic FTY720 application. CONCLUSION: Our findings revealed the inhibitory effect of FTY720 on GBM, and the great ability of GF2-FTY720-LPs to target GBM. GF2-FTY720-LPs penetrate the blood-brain barrier without relying on specific conditions such as a magnetic field, light, or heat. GF2-FTY720-LPs achieved precise localization by targeting the highly expressed GLUT1 in GBM cells, and efficiently released drugs in the acidic tumor microenvironment, which significantly reduced the off-target toxicity and enhanced the antitumor efficacy compared with traditional chemotherapy drugs. In summary, our study provides new insights and a theoretical basis for selecting and researching GBM treatment.