PANoptosis-Related Molecular Subtyping and a Subtype-Derived Prognostic Signature for Survival Prediction in Clear Cell Renal Cell Carcinoma

IntroductionPANoptosis is an inflammatory form of programmed cell death integrating pyroptosis, apoptosis, and necroptosis, but its prognostic and immunological significance in clear cell renal cell carcinoma (ccRCC) remains unclear.MethodsIn this retrospective study, candidate PANoptosis-related genes (candidate PRGs) were identified from GeneCards and TCGA databases. Prognosis-related candidate PRGs were screened using copy number variation and Cox regression analyses, followed by consensus clustering to establish PANoptosis-related molecular subtypes. Differentially expressed genes (DEGs) between subtypes were used to construct a prognostic model using LASSO and Cox regression. Survival, immune infiltration, somatic mutation, alternative polyadenylation, and drug sensitivity analyses were subsequently performed. The model was externally assessed in an independent GEO cohort, while single-cell RNA sequencing (scRNA-seq) and in vitro experiments were used to investigate the cellular distribution and biological functions of model-related genes.ResultsFifteen candidate PRGs were identified, 11 of which were associated with overall survival. Consensus clustering identified two PANoptosis-related molecular subtypes and 218 subtype-related DEGs. A six-gene prognostic model comprising CDC20, ISG15, IL20RB, RGS1, PDK4, and SLC16A12 was developed using subtype-related DEGs and stratified patients into high- and low-risk groups. High-risk patients had significantly shorter overall survival, and the model showed good prognostic performance in the TCGA-KIRC cohort, with 1-, 3-, and 5-year AUCs of 0.769, 0.735, and 0.740, respectively. The two risk groups differed in immune infiltration, somatic mutations, alternative polyadenylation, and predicted drug sensitivity. scRNA-seq showed that monocytes had higher prognostic signature scores, particularly C1QC monocytes. In vitro, modulating model-related genes affected ccRCC cell proliferation, migration, and invasion, with some changes accompanied by altered PANoptosis-related protein expression.ConclusionPANoptosis-related molecular subtypes may be associated with prognosis and the tumor microenvironment in ccRCC. The six-gene prognostic model may provide a reference for risk stratification and prognostic prediction.