Endometrial cancer (EC) is a fatal female reproductive tumor. Bioinformatic tools are increasingly developed to screen out molecular targets related to EC. In this study, GSE17025 and GSE40032 were obtained from Gene Expression Omnibus (GEO). “limma” package and Venn diagram tool were used to identify hub genes. FunRich was used for functional analysis. Retrieval of Interacting Genes Database (STRING) was used to analyze protein‐protein interaction (PPI) complex. Cancer Genome Atlas (TCGA), GEPIA, immunohistochemistry staining, and ROC curve analysis were carried out for validation. Univariate and multivariate regression analyses were performed to predict the risk score. Compound muscle action potential (CMap) was used to find potential drugs. GSEA was also done. We retrieved seven oncogenes which were upregulated and hypomethylated and 12 tumor suppressor genes (TSGs) which were downregulated and hypermethylated. The upregulated and hypomethylated genes were strikingly enriched in term “immune response” while the downregulated and hypermethylated genes were mainly focused on term “aromatic compound catabolic process.” TCGA and GEPIA were used to screen out EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1. Among them, ESPL1 and ROR2 were identified by Cox regression analysis and were used to construct prognostic risk model. The result showed that ESPL1 was a negative independent prognostic factor. Cmap identified aminoglutethimide, luteolin, sulfadimethoxine, and maprotiline had correlation with EC. GSEA results showed that “hedgehog signaling pathway” was enriched. This research inferred potential aberrantly methylated DEGs and dysregulated pathways may participate in EC development and firstly reported eight hub genes, including EDNRB, CDO1, NDN, PLCD1, ROR2, ESPL1, PRAME, and PTTG1 that could be used to predict EC prognosis. Aminoglutethimide and luteolin may be used to fight against EC.
