Development of a novel prognostic model based on TRPM4-Induced sodium overload–mediated cell death in kidney cancer

Background Clear cell renal cell carcinoma (ccRCC) is the predominant subtype of kidney cancer. Its incidence and mortality rates remain consistently high, creating an urgent need to identify novel biomarkers and therapeutic targets. Necrosis by sodium overload (NECSO), mediated by the TRPM4 channel, represents a newly discovered form of cell death; however, its role in ccRCC remains unclear. Methods We performed a pan-cancer analysis of TRPM4 using TCGA data. GO, and KEGG enrichment analyses were employed to investigate TRPM4-associated functions and pathways in KIRC. Three machine learning algorithms (plsRcox, GBM, and CoxBoost) were integrated to identify 14 pivotal genes for constructing a comprehensive NECSO Score. TIME was assessed using CIBERSORT, xCell, and ESTIMATE algorithms. Finally, the biological functions of TRPM4 were validated in 769-P and A498 cells through in vitro experiments. Results Pan-cancer analysis revealed that TRPM4 was significantly downregulated in KIRC, and its high expression was associated with prolonged RFS. The NECSO Score, derived from the 14-gene signature, served as an independent protective prognostic factor. A high NECSO Score was correlated with an activated immune microenvironment, characterized by increased infiltration of CD8 + T cells and Th1 cells. In vitro assays confirmed that TRPM4 overexpression suppressed the proliferation, migration, and clonogenicity of ccRCC cells while promoting apoptosis. Furthermore, TRPM4 overexpression synergized with the sodium overload inducer Necrocide-1 (NC1) to enhance anti-tumor efficacy. Conclusion This study systematically unveils the tumor-suppressive role of TRPM4 in ccRCC and innovatively establishes the NECSO Score as a robust prognostic model. This score not only accurately predicts patient outcomes but also illuminates the potential link between sodium ion homeostasis and the tumor immune landscape. Targeting TRPM4 and NECSO may represent a promising therapeutic avenue for ccRCC.