Comprehensive analysis of PANoptosis-related molecular subtypes and prognostic model development of clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) exhibits strong heterogeneity and variable therapeutic responses. PANoptosis, an integrated form of inflammatory programmed cell death, may influence tumor immunity and prognosis, yet its role in ccRCC remains unclear. METHODS: Multi-omics data from TCGA database were analyzed to characterize PANoptosis-related genes (PRG), define molecular and gene subtypes, and construct a prognostic PRG score using Cox and LASSO regression. Immune infiltration, drug sensitivity, and predicted immunotherapy response were evaluated. Single-cell RNA sequencing analysis was used to map PRG expression across cell populations. In vitro experiments were performed to validate RBCK1 function in ccRCC. RESULTS: 14 PRG showed marked CNV alterations and differential expression. Three PRG molecular subtypes displayed distinct survival outcomes and immune landscapes. A three-gene PRG score (RIPK1, PYCARD, RBCK1) independently stratified prognosis and correlated with immune infiltration, mutation burden, and therapy sensitivity. Lower scores predicted better immunotherapy response and higher drug sensitivity. Single-cell analysis revealed broad PRG expression across macrophages, epithelial cells, endothelial cells, and stem-like cells. RBCK1 was significantly upregulated in ccRCC and promoted proliferation and migration, while its knockdown inhibited tumor cell growth. CONCLUSIONS: We delineated the PANoptosis landscape in ccRCC and developed a robust PRG score with strong prognostic and immunological relevance. RBCK1 functions as a key oncogenic regulator and potential therapeutic target. These findings offer a valuable framework for precision risk assessment and treatment optimization in ccRCC.