There is a surprising paucity of studies investigating the potential mechanism of SKA3 in the progression and prognosis of kidney renal papillary cell carcinoma (KIRP).We used TCGA and other databases to analyze the expression, clinical value, and potential mechanisms of SKA3 in KIRP patients. We also explored therapeutic agents for KIRP through GSCALite.SKA3 mRNA expression was significantly upregulated and the area under the curve was 0.792 (95% CI 0.727-0.856). Increased SKA3 expression was related to shorter overall survival, disease-specific survival and progression-free survival. Hub genes in protein-protein interactions were CDK1, CDC20, CCNB1, CCNA2, BUB1, AURKB, BUB1B, PLK1, CCNB2, and MAD2L1, which were differentially expressed and also associated with KIRP prognosis. Gene-set enrichment analysis indicated that E2F targets, epithelial-mesenchymal transition, glycolysis, the WNT signaling pathway, and other pathways were highly enriched upon SKA3 upregulation. Gene-set variation analysis of SKA3 and its ten hub genes showed that the significant correlation of cancer-related pathways included the cell cycle, DNA damage, hormone androgen receptor, hormone estrogen receptor, PI3K/Akt, and Ras/MAPK. In addition, we found that MEK inhibitors, ie, trametinib, selumetinib, PD0325901, and RDEA119, may be feasible targeting agents for KIRP patients.SKA3 might contribute to poor prognosis of KIRP through cell cycle, DNA damage, hormone androgen receptor, hormone estrogen receptor, PI3K/Akt, and RAS/MAPK. SKA3 potentially serves as a prognostic biomarker and target for KIRP.© 2021 Feng et al.