ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Molecular and Cellular Pathology
This article is part of the Research TopicGenetics in the Onset and Progression of Urinary System Diseases: Pathological Role and Molecular MechanismView all 4 articles
Development of a Novel Prognostic Model Based on TRPM4-Induced Sodium Overload–Mediated Cell Death in kidney Cancer
Provisionally accepted
- Second Hospital of Tianjin Medical University, Tianjin, China
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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.
Keywords: bioinformatics, Cell Death, Clear cell renal cell carcinoma (ccRCC), Prognostic model, TRPM4, Tumor immune microenvironment
Received: 27 Nov 2025; Accepted: 18 Dec 2025.
Copyright: © 2025 Wang, Zhao, Zhou, Chen, Zhang, Du and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Changwen Zhang
E Du
Longchao Zhang
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