Background <p>Endometrial cancer (EC) is a common gynecological tumor. Insulin resistance (IR) increases the risk of EC. However, the common molecular basis between the two remains unclear. This study aims to screen the common differential expression genes (DEGs) between the two diseases and construct a prognostic risk model.</p> Methods <p>We obtained gene expression profiles and clinical information of patients with IR and EC from GEO and TCGA datasets. We performed differential analysis to discover the shared DEGs between IR and EC. Subsequently, the interactions among overlapping DEGs, along with their biological functions and genetic mutations in EC, were comprehensively analyzed via protein–protein interaction (PPI) network, function enrichment analyses, and genetic mutation analyses. Then, machine-learning algorithms were employed to figure out genes significantly associated with survival. For clinical application, we constructed a prognostic risk model and also compared tumor-infiltrating immune cells (TIICs) and genetic mutation between high- and low-risk groups. Finally, we screened one of the most important markers in the prognostic signature to investigate its expression-prognosis pattern, biological function, and underlying mechanism.</p> Results <p>Our analysis identified 20 co-upregulated genes and 32 co-downregulated genes of IR and EC. In addition, the two subnetworks and the top 20 top genes were obtained through PPI analysis, while the construction of extracellular matrix and immune response were the most enriched functions of DEGs. Filtered by random forest, gradient boosting machine, and extreme gradient boosting, six upregulated markers (ACTL8, WNT7A, CTSV, MMP9, CNIH2, and PLAUR) and four downregulated markers (COL6A6, MYOC, PHLDB1, and FIBIN), were defined as the characteristic genes for the prognosis of EC patients. The risk prediction model constructed by these ten genes had good predictive value in prognosis of EC patients and was related to immune regulation and genetic mutation. ACTL8 was further studied as the most significant marker among 10-gene signature. The correlation between the upregulation of ACTL8 and the poor prognosis of EC patients suggested its carcinogenic effect, which was correlated to its regulation of cilium movement.</p> Conclusion <p>Our findings suggest that there are common molecular profiles between IR and EC. IR-related prognostic model represents an excellent prognosis predictor and immune-related biomarker, which can be applied to risk stratification and precise treatment of EC patients with IR.</p>