Objective <p>Pyroptosis, an important form of cell death, remains to be explored for its significance in renal cell carcinoma.</p> Methods <p>We conducted a Summary-data-based Mendelian Randomization (SMR) analysis to investigate the association between pyrogenic gene-related SNPs and renal cell carcinoma outcomes, identified core genes with significant associations, and then performed transcriptomic profiling analysis of renal clear cell carcinoma using TCGA data to assess diagnostic and prognostic potential. Subsequently, we explored the functional mediation of core genes through enrichment analysis and GSEA, and analyzed immune function using Cibersort and ssGSEA. We then presented the expression patterns of core genes using single-cell data, and finally analyzed the differences in chemotherapy sensitivity between high- and low-expression groups of core genes using oncoPredict, and validated the potential for targeting core genes with molecular drugs.</p> Results <p>Through SMR and MR, we identified CASP9 as a key factor in pyroptosis-related processes in renal cell carcinoma, acting as a protective factor for renal cell carcinoma outcomes and demonstrating excellent diagnostic potential. Survival analysis revealed that high CASP9 expression in early-stage renal cell carcinoma was associated with better prognosis, whereas the opposite was true in advanced-stage renal cell carcinoma. Functional enrichment analysis indicated that CASP9 may mediate multiple pathways, including epithelial-mesenchymal transition. Immune infiltration analysis highlighted a strong correlation between CASP9 expression and natural killer cell abundance. Finally, we analyzed differences in chemotherapy sensitivity between high- and low-CASP9 expression groups and identified potential drugs for molecular docking validation.</p> Conclusion <p>CASP9 can serve as a potential target for renal clear cell carcinoma, with potential for guiding diagnosis, prognosis, and chemotherapy selection.</p>