Abstract: Based on single-cell sequencing data, this study explored the expression difference and mechanism of SENP2 in three different subtypes of renal cell carcinoma（RCC）. The dimension reduction visualization of UMAP and the screening of differentially expressed genes（DEGs） were carried out by R language. Functional annotation and enrichment analysis of DEGs were carried out, and protein-protein interaction（PPI） network was constructed. Hub genes were screened through Cytoscape software. By analyzing the relationship between SENP2 expression difference and survival prognosis and clinical stage of three RCC subtypes, the role of SENP2 in different subtypes was revealed. By analyzing the correlation between SENP2 and its interacting genes, the regulatory mechanism of SENP2 was explored causing the difference in survival prognosis and clinical stage of three different RCC subtypes. Finally, immunohistochemistry was performed on SENP2 in kidney renal clear cell carcinoma（KIRC）. The results of this study showed that gene expression in three RCC subtypes was different. The DEGs in the three RCC subtypes were significantly enriched in biological processes such as cell proliferation, protein metabolism, cell senescence and TP53 regulation. SENP2 was locked by screening the hub gene. Survival analysis and clinical staging analysis results showed that, in KIRC, with the increase of clinical staging, the expression of SENP2 gradually decreased, and the survival prognosis of patients became worse. In kidney chromophobe（KICH）, the expression of SENP2 was in direct proportion to the survival prognosis of patients, but not related to the clinical staging. In kidney renal papillary cell carcinoma（KIRP）, the expression of SENP2 was in inverse proportion to the survival prognosis of patients. The higher the expression of SENP2, the worse the prognosis of patients, and there was no correlation with clinical stage. The study on the correlation between SENP2 and its interacting genes showed that in KIRC and KICH, SENP2 positively regulated the tumor suppressor gene TP53 by SUMOylation modification, while in KIRP, SENP2 negatively regulated TP73 by SUMOylation modification, a member of TP53 family, which led to the difference of SENP2 in regulating the three subtypes of RCC. Immunohistochemical results showed that SENP2 was low expressed in KIRC and was independent of age, sex and tumor size. In summary, SENP2 participates in the occurrence and development of three subtypes of RCC through different regulatory mechanisms, and is expected to become a tumor marker for judging RCC, providing a new idea for the study of related mechanisms.