〔Abstract〕 Objective To investigate the molecular mechanism of ferroptosis in glioblastoma(GBM) and to provide insights for identifying new therapeutic targets. Methods GSE108474 was selected from gene expression omnibus(GEO) database and differentially expressed genes(DEGs) in GBM were obtained by using GEO2R, compared with the gene set in the Ferroptosis database(FerrDb) to identify ferroptosis-related gene. GO and KEGG enrichment analyses were conducted using DAVID database. A protein-protein interaction network was created using String website. Hub genes with high connectivity were confirmed using Cytoscape software. Prognostic and immune infiltration analyses were performed using TIMER website. RNA expression levels and gene correlation analyses were carried out using GEPIA website. Differential expression of hub gene proteins was analyzed by using the HPA database. Tumor immune characteristic correlations were examined using TISIDB database. Differences in mRNA expression of hub genes between tumor cells A172 and U251MG and normal astrocytes HA1800 were compared using the quantitative real-time PCR. Results Out of 5 331 differentially expressed genes, 114 were related to ferroptosis. GO and KEGG enrichment analysis suggested that these 114 genes might play roles in positive regulation of gene expression, and affect tumor progression through ferroptosis and autophagy pathways. 10 hub genes were identified in the protein-protein interaction network, among which cluster of differentiation 44(CD44), murine double minute 2(MDM2) and signal transducer and activator of transcription 3(STAT3) were found to be highly expressed in tumors with lower survival rates.CD44,MDM2 and STAT3mRNA expression were higher in GBM cells compared to normal cells. Protein expression of CD44, MDM2 and STAT3 was higher in high-grade glioma tissues than that in normal tissues. The expression of three genes in the tumor was negatively correlated with ferroptosis. Immune infiltration analysis revealed thatCD44,MDM2andSTAT3in the tumor were related to the infiltration of neutrophils, CD4+T cells, and dendritic cells, and the expression of three genes was related to various chemokines and their receptors. Conclusion CD44,MDM2andSTAT3may play a role in tumor ferroptosis and immune regulation, which have the potential to become a therapeutic target for GBM.