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

Wei Wang1, Duo Zhao1, Zijun Zhou1

  • 1Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.

Frontiers in Cell and Developmental Biology
|January 26, 2026
PubMed
Abstract

Insights

Clear cell renal cell carcinoma (ccRCC) has high mortality. TRPM4 channel activity, linked to sodium overload cell death (NECSO), shows a tumor-suppressive role in ccRCC, offering a new prognostic score and therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Clear cell renal cell carcinoma (ccRCC) remains a significant health challenge with high incidence and mortality.
  • Novel biomarkers and therapeutic targets are urgently needed for ccRCC.
  • The role of TRPM4 channel-mediated necrosis by sodium overload (NECSO) in ccRCC is currently unknown.

Purpose of the Study:

  • To investigate the role of the TRPM4 channel in ccRCC.
  • To develop a prognostic model based on TRPM4-associated genes.
  • To explore the relationship between TRPM4, NECSO, and the tumor immune microenvironment in ccRCC.

Main Methods:

  • Pan-cancer analysis of TRPM4 expression in KIRC using TCGA data.
  • Gene Ontology (GO) and KEGG pathway enrichment analyses.
  • Machine learning algorithms (plsRcox, GBM, CoxBoost) to develop a 14-gene NECSO Score.
  • Tumor Immune Microenvironment (TIME) assessment using CIBERSORT, xCell, and ESTIMATE.
  • In vitro validation of TRPM4 functions in ccRCC cell lines.

Main Results:

  • TRPM4 was significantly downregulated in KIRC, with high expression correlating with improved relapse-free survival (RFS).
  • The developed NECSO Score, based on 14 genes, independently predicted better outcomes and was linked to an activated immune microenvironment.
  • TRPM4 overexpression suppressed ccRCC cell proliferation, migration, and clonogenicity, while enhancing apoptosis and synergizing with Necrocide-1 (NC1) to improve anti-tumor effects.

Conclusions:

  • TRPM4 exhibits a tumor-suppressive role in ccRCC.
  • The NECSO Score serves as a robust prognostic tool and highlights the connection between sodium homeostasis and ccRCC immunity.
  • Targeting TRPM4 and NECSO presents a potential therapeutic strategy for ccRCC.
Keywords:
TRPM4bioinformaticscell deathclear cell renal cell carcinoma (ccRCC)prognostic modeltumor immune microenvironment

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