GSN liquid-liquid phase separation induces PANoptosis by inhibiting YAP-dependent glycolysis to alleviate the progression of clear cell renal cell carcinoma.

This study was carried out to screen PANoptosis-related biomarker genes and the involved underlying mechanism in clear cell renal cell carcinoma (ccRCC). Differentially expressed (DE) PANoptosis-related genes were identified. Then prognostic biomarker genes were screened, and used to construct a prognostic model. The predictive ability of the model was explored by receiver operating characteristic (ROC) curves. Then the correlation between risk score with clinical features and immune cell infiltration were evaluated. The expression level and prognosis of gelsolin (GSN) were examined in datasets. Furthermore, in vivo and in vitro experiments were employed to investigate underlying mechanisms. ScRNA-seq analysis uncovered that PANoptosis scores varied significantly across 9 cell types in the tumor microenvironment. A total of 26 DE-PANoptosis-related genes were identified by intersecting DEGs and PANoptosis-related genes. Then 3 prognosis biomarker genes were screened and used to build the prognostic model, namely TLR3, GSN and TNFRSF1A. The risk score was associated with tumor grade, stage (I, II, III, IV), pathologic T-Stage, etc, and also significantly correlated with immune cells and expression of immune checkpoint proteins. In addition, GSN was upregulated in ccRCC, and high expression of GSN indicated a favorable OS. In vivo and in vitro experiments revealed that GSN liquid-liquid phase separation (LLPS) directly induces PANoptosis in ccRCC by inhibiting YAP-dependent glycolysis. In conclusion, using TLR3, GSN and TNFRSF1A, the established PANoptosis-related prognostic model was established and showed good predictive performance for predicting prognosis of ccRCC patients. GSN LLPS directly induces PANoptosis in ccRCC by inhibiting YAP-dependent glycolysis.