Objective <p>Through transcriptomic analysis and expression level validation, ubiquitin-related genes with overlapping expression profiles between renal cell carcinoma and periodontitis were identified.</p> Materials and methods <p>RNA-seq datasets of renal cell carcinoma from The Cancer Genome Atlas (TCGA) and periodontitis from the Gene Expression Omnibus (GEO) were analyzed to identify differentially expressed genes (DEGs) in each disease. A total of 322 ubiquitination-related genes were integrated with the identified DEGs to screen ubiquitination-related genes with overlapping expression patterns between renal cell carcinoma and periodontitis. Survival analysis, functional enrichment analysis, protein–protein interaction (PPI) network construction, and subsequent expression validation via quantitative real-time PCR (qPCR) and immunohistochemistry (IHC) were performed on these overlapping genes in clinical samples.</p> Results <p>In this study, differentially expressed genes (DEGs) in renal cell carcinoma and periodontitis were screened by analyzing the TCGA-KIRC dataset and periodontal disease datasets from the GEO database. Meanwhile, 332 ubiquitination genes collected from published literature were intersected separately with DEGs of renal cell carcinoma and periodontitis. Subsequent Venn diagram analysis identified 10 co-regulated ubiquitination-related genes (ALDOB, FABP5, IFI16, IKZF1, LGALS1, LSP1, MNDA, RPL13, VIM, WAS) as crosstalk genes between renal cell carcinoma and periodontitis. To systematically screen the genes with the strongest comprehensive regulatory capacity, the above 10 crosstalk genes were comprehensively evaluated in parallel from two independent and critical dimensions. In terms of the shared molecular mechanisms underlying periodontitis and renal cell carcinoma, six genes (IKZF1, LGALS1, LSP1, MNDA, VIM and WAS) were consistently upregulated in both disease tissues, indicating their potential involvement in the common pathogenesis of the two diseases. Tumor mutation analysis further indicated that the above 10 URGs were significantly correlated with the tumor immune microenvironment. Functional enrichment analysis revealed that these genes may affect disease progression via ubiquitin-mediated proteolysis and the p53 signaling pathway.With regard to the correlation between gene expression levels and survival outcomes of patients with renal cell carcinoma, subsequent Kaplan–Meier survival analysis verified that among the 10 co-regulated ubiquitination-related genes, six genes (ALDOB, FABP5, IFI16, LGALS1, RPL13, WAS) exhibited significant correlations with the prognosis of RCC.LASSO regression was subsequently performed to screen the four genes (ALDOB, IFI16, WAS, IKZF1) that showed significance in multivariate regression analysis. Finally, WAS and IKZF1 were identified as the key ubiquitination regulatory genes underlying renal cell carcinoma and periodontitis.Consistent high expression levels of WAS and IKZF1 in both periodontitis and renal cell carcinoma tissues were verified by qPCR and immunohistochemistry (IHC), compared with normal control tissues. The protein–protein interaction (PPI) network and miRNA-prognostic gene regulatory network were constructed using Cytoscape software.</p> Conclusion <p>This study firstly reveals that WAS and IKZF1 are ubiquitin-related genes with overlapping expression patterns in renal cell carcinoma and periodontitis, suggesting that they may participate in the occurrence and progression of the two diseases by regulating ubiquitination-related pathways. This finding not only enriches our understanding of the molecular expression characteristics of renal cell carcinoma and periodontitis but also verifies the potential of WAS and IKZF1 as cross-disease targets. It provides novel insights into the screening of potential biomarkers for these two diseases, and offers preliminary references for further exploring the clinical translational value of ubiquitination-related genes in renal cell carcinoma and periodontitis.</p> Clinical trial number <p>Not applicable.</p> Graphical Abstract <p></p>