PRR15 suppresses renal cell carcinoma progression via the NF-κB/FDX1 axis to induce cuproptosis and mitochondrial dysfunction

  • Oncogene. 2026 Mar;45(9):840-855. doi: 10.1038/s41388-026-03683-2.
Jialu Ma  #  1 ,  Jianqiao Li  #  1 ,  Zhihao Bo  #  1 ,  Shiyue Zhang  1 ,  Yuankang Feng  1 ,  Xinyu Liu  2 ,  Yihan Dong  2 ,  Jiaxin Li  2 ,  Shaomin Guo  2 ,  Yuejing Pan  2 ,  Huamao Jiang  3 ,  Rui Wang  4 ,  Dan Yue  5 ,  Yong Wang  6
Affiliations
  • 1. Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
  • 2. Division of Medical Technology, Tianjin Medical University, Tianjin, China.
  • 3. Department of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China.
  • 4. Division of Medical Technology, Tianjin Medical University, Tianjin, China. [email protected].
  • 5. Division of Medical Technology, Tianjin Medical University, Tianjin, China. [email protected].
  • 6. Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China. [email protected].
  • # Contributed equally.
PMID: 41673093 DOI: 10.1038/s41388-026-03683-2
Abstract

Cuproptosis is involved in the proliferation, metastasis, and drug resistance formation development of renal cell carcinoma (RCC) by regulating lipid metabolism and oxidative stress levels in the tumor microenvironment, with Ferredoxin 1 (FDX1) as a core regulator. Proline-rich 15 (PRR15) is a proline-rich protein, that we previously found to inhibit the malignant progression of triple-negative breast Cancer through the regulation of the phosphatidylinositol 3-kinase (PI3K) pathway and epithelial-mesenchymal transition (EMT) pathway. However, the role of PRR15 in Cuproptosis and its molecular mechanisms remain unknown. This study found confirmed that PRR15 promotes Cuproptosis and mitochondrial damage in RCC cells and inhibits tumor proliferation and metastasis, as demonstrated in vivo and in vitro. When RCC develops, PRR15 silencing activates the nuclear factor kappa-B (NF-κB) signaling pathway, which inhibits FDX1 expression, ultimately blocking the Cuproptosis process and increasing tumor invasiveness. Conversely, overexpression of PRR15 reverses this phenotype. This study reveals for the first time the regulatory mechanism of the PRR15/NF-κB/FDX1 axis in Cuproptosis in RCC, providing a new strategy for the treatment of RCC patients.

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