AbstractAimsGlioblastoma (GBM) is the most common malignant brain tumor with an adverse prognosis in the central nervous system. Traditional histopathological diagnosis accompanied by subjective deviations cannot accurately reflect tumor characteristics for clinical guidance. DNA methylation plays a critical role in GBM genesis. The focus of this project was to identify an effective methylation point for the classification of gliomas, the interactions between DNA methylation and potential epigenetic targeted therapies for clinical treatments.MethodsThree online (TCGA, CGGA, and REMBRANDT) databases were employed in this study. T‐test, Venn analysis, univariate cox analysis, and Pearson's correlation analysis were adopted to screen significant prognostic methylation genes. Clinical samples were collected to determine the distributions of LRRFIP1 (Leucine Rich Repeat of Flightless‐1 Interacting Protein) protein by immunohistochemistry assay. Kaplan–Meier survival and Cox analysis were adopted to evaluate the prognostic value of LRRFIP1. Nomogram model was used to construct a prediction model. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway were performed to explore functions and related mechanisms of LRRFIP1 in gliomas.ResultsOur results showed that 16 genes were negatively connected with their methylation level and correlated with clinical prognosis of GBM patients. Among them, LRRFIP1 expression showed the highest correlation with its methylation level. LRRFIP1 was highly expressed in WHO IV, mesenchymal, and IDH wild‐type subtype. LRRFIP1 expression was an independent risk factor for OS (overall survival) in gliomas.ConclusionLRRFIP1 is an epigenetically regulated gene and a potential prognostic biomarker for glioma. Our research may be beneficial to evaluate clinical efficacy, assess the prognosis, and provide individualized treatment for gliomas.