Glioblastoma multiforme (GBM) is the most common primary CNS cancer and has a poor prognosis. This study searched for significant genes and the mechanisms involved in GBM. We used the Gene Expression Omnibus (GEO) to test the WHO normal and IV glioma database, used R tool to identify the significant gene, and finally, combined these with The Cancer Genome Atlas (TCGA) to verify the significant genes. Subsequently, we explored the biological mechanisms involved. Phytanoyl-CoA 2-hydroxylase-interacting protein-like gene (PHYHIPL) is downregulated in grade IV glioma (GBM). The downregulation of PHYHIPL in GBM is accompanied by poor overall survival in the TCGA database, which indicates that PHYHIPL is a protection gene in GBM development. Bioinformatics analysis shows that the poor prognosis with downregulated PHYHIPL may be the result of the TNF signaling pathway and the IL-17 signaling pathway, but good prognosis accompanied by upregulated PHYHIPL may be the result of retrograde endocannabinoid signaling and the cAMP signaling pathway. Protein-protein interactions (PPI) net indicated that PHYHIPL may play a vital role in cell metabolism, and we hypothesize that the downregulation mechanism may be the result of mutations of the ß-catenin gene and the endogenous siRNA, as shown in previous studies. PHYHIPL may be a target gene for the treatment and prognosis of GBM.