Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Oncogene volume 45, pages 840–855 (2026) Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: PRR15 is downregulated in RCC.
The alternative text for this image may have been generated using AI.
Fig. 2: Correlation of PRR15 expression with clinical features in RCC.
The alternative text for this image may have been generated using AI.
Fig. 3: PRR15 silencing is required for RCC initiation and progression.
The alternative text for this image may have been generated using AI.
Fig. 4: PRR15 silencing promotes mitochondrial function in vitro.
The alternative text for this image may have been generated using AI.
Fig. 5: Cuproptosis is essential for PRR15-mediated mitochondrial alterations.
The alternative text for this image may have been generated using AI.
Fig. 6: PRR15 upregulates the cuproptosis-related gene FDX1 via the NF-κB pathway.
The alternative text for this image may have been generated using AI.
Fig. 7: PRR15 promotes cuproptosis in vivo.
The alternative text for this image may have been generated using AI.

Similar content being viewed by others

Data availability

The authors declare that the data supporting the findings of this study are available within the article and its Supplementary Information files. All relevant data are available from the authors upon request.

References

  1. Rose TL, Kim WY. Renal cell carcinoma: a review. JAMA. 2024;332:1001–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Patel HD, Gupta M, Joice GA, Srivastava A, Alam R, Allaf ME, et al. Clinical stage migration and survival for renal cell carcinoma in the United States. Eur Urol Oncol. 2019;2:343–8.

    Article  PubMed  Google Scholar 

  3. Strohbehn GW, Goldstein DA. Registration trials in countries without access to US standards of care - pitfalls of interpretation. Nat Rev Clin Oncol. 2021;18:395–6.

    Article  PubMed  CAS  Google Scholar 

  4. Wang Y, Suarez ER, Kastrunes G, de Campos NSP, Abbas R, Pivetta RS, et al. Evolution of cell therapy for renal cell carcinoma. Mol Cancer. 2024;23:8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chakraborty S, Balan M, Sabarwal A, Choueiri TK, Pal S. Metabolic reprogramming in renal cancer: events of a metabolic disease. Biochim Biophys Acta Rev Cancer. 2021;1876:188559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Coffey NJ, Simon MC. Metabolic alterations in hereditary and sporadic renal cell carcinoma. Nat Rev Nephrol. 2024;20:233–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Rathmell WK, Rathmell JC, Linehan WM. Metabolic pathways in kidney cancer: current therapies and future directions. J Clin Oncol. 2018;JCO2018792309 https://doi.org/10.1200/JCO.2018.79.2309IF.

  8. Bezwada D, Perelli L, Lesner NP, Cai L, Brooks B, Wu Z, et al. Mitochondrial complex I promotes kidney cancer metastasis. Nature. 2024;633:923–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Tsvetkov P, Coy S, Petrova B, Dreishpoon M, Verma A, Abdusamad M, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375:1254–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Tian S, Wang R, Wang Y, Chen R, Lin T, Xiao X, et al. p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization. Int J Biol Sci. 2024;20:516–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Lei G, Tang L, Yu Y, Bian W, Yu L, Zhou J, et al. The potential of targeting cuproptosis in the treatment of kidney renal clear cell carcinoma. Biomed Pharmacother. 2023;167:115522.

    Article  PubMed  CAS  Google Scholar 

  12. Tsvetkov P, Detappe A, Cai K, Keys HR, Brune Z, Ying W, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol. 2019;15:681–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Panaiyadiyan S, Quadri JA, Nayak B, Pandit S, Singh P, Seth A, et al. Association of heavy metals and trace elements in renal cell carcinoma: A case-controlled study. Urol Oncol. 2022;40:111.e11–8.

    Article  PubMed  CAS  Google Scholar 

  14. Yang Q, Wang Y, Yang Q, Gao Y, Duan X, Fu Q, et al. Cuprous oxide nanoparticles trigger ER stress-induced apoptosis by regulating copper trafficking and overcoming resistance to sunitinib therapy in renal cancer. Biomaterials. 2017;146:72–85.

    Article  PubMed  CAS  Google Scholar 

  15. Meunier D, Peters T, Luttges A, Curfs J, Fundele R. Preferential expression of the G90 gene in post-mitotic cells during mouse embryonic development. Anat Embryol. 2003;207:109–17.

    Article  CAS  Google Scholar 

  16. Krause R, Hemberger M, Himmelbauer H, Kalscheuer V, Fundele RH. Identification and characterization of G90, a novel mouse RNA that lacks an extensive open reading frame. Gene. 1999;232:35–42.

    Article  PubMed  CAS  Google Scholar 

  17. Purcell SH, Cantlon JD, Wright CD, Henkes LE, Seidel GE Jr., Anthony RV. The involvement of proline-rich 15 in early conceptus development in sheep. Biol Reprod. 2009;81:1112–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Gates KC, Goetzmann LN, Cantlon JD, Jeckel KM, Anthony RV. Effect of proline rich 15-deficiency on trophoblast viability and survival. PLoS One. 2017;12:e0174976.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Guo F, Ma J, Li C, Liu S, Wu W, Li C, et al. PRR15 deficiency facilitates malignant progression by mediating PI3K/Akt signaling and predicts clinical prognosis in triple-negative rather than non-triple-negative breast cancer. Cell Death Dis. 2023;14:272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Wang R, Lin T, Liu Y, Wang H, Liu X, Dong Y, et al. Programmed Cell Death Protein 10 (PDCD10) regulates vesicle trafficking and contributes to the progression of clear cell renal cell carcinoma. J Extracell Vesicles. 2025;14:e70108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Liao Q, Deng J, Tong J, Gan Y, Hong W, Dong H, et al. p53 induces circFRMD4A to suppress cancer development through glycolytic reprogramming and cuproptosis. Mol Cell. 2025;85:132–49.e7.

    Article  PubMed  CAS  Google Scholar 

  22. Wang W, Lu K, Jiang X, Wei Q, Zhu L, Wang X, et al. Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer. J Exp Clin Cancer Res. 2023;42:142.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zvirblyte J, Nainys J, Juzenas S, Goda K, Kubiliute R, Dasevicius D, et al. Single-cell transcriptional profiling of clear cell renal cell carcinoma reveals a tumor-associated endothelial tip cell phenotype. Commun Biol. 2024;7:780.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Li Z, Zhou H, Zhai X, Gao L, Yang M, An B, et al. MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function. Cell Death Dis. 2023;14:733.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Capitanio U, Bensalah K, Bex A, Boorjian SA, Bray F, Coleman J, et al. Epidemiology of renal cell carcinoma. Eur Urol. 2019;75:74–84.

    Article  PubMed  Google Scholar 

  26. Cowman SJ, Koh MY. Revisiting the HIF switch in the tumor and its immune microenvironment. Trends Cancer. 2022;8:28–42.

    Article  PubMed  CAS  Google Scholar 

  27. Lee CH, Voss MH, Carlo MI, Chen YB, Zucker M, Knezevic A, et al. Phase II trial of cabozantinib plus nivolumab in patients with non-clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol. 2022;40:2333–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Pal SK, Tran B, Haanen J, Hurwitz ME, Sacher A, Tannir NM, et al. CD70-Targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. 2024;14:1176–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Meunier D, Patra K, Smits R, Hagebarth A, Luttges A, Jaussi R, et al. Expression analysis of proline rich 15 (Prr15) in mouse and human gastrointestinal tumors. Mol Carcinog. 2011;50:8–15.

    Article  PubMed  CAS  Google Scholar 

  30. Xing S, Wang Y, Hu K, Wang F, Sun T, Li Q. WGCNA reveals key gene modules regulated by the combined treatment of colon cancer with PHY906 and CPT11. Biosci Rep. 2020;40:BSR20200935

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wang Q, Yu X, Yang N, Xu L, Zhou Y. LncRNA AC007255.1, an immune-related prognostic enhancer RNA in esophageal cancer. PeerJ. 2021;9:e11698.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Yu Z, Qiu B, Li L, Xu J, Zhou H, Niu T. An emerging prognosis prediction model for multiple myeloma: Hypoxia-immune related microenvironmental gene signature. Front Oncol. 2022;12:992387.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Um SW, Kim Y, Lee BB, Kim D, Lee KJ, Kim HK, et al. Genome-wide analysis of DNA methylation in bronchial washings. Clin Epigenetics. 2018;10:65.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ji Y, Zhang H, Gong FL, Liang JL, Wang SF, Sang YH, et al. The expression and functional role of proline-rich 15 in non-small cell lung cancer. Cell Death Dis. 2025;16:83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Long S, Wang Y, Chen Y, Fang T, Yao Y, Fu K. Pan-cancer analysis of cuproptosis regulation patterns and identification of mTOR-target responder in clear cell renal cell carcinoma. Biol Direct. 2022;17:28.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Yuan H, Qin X, Wang J, Yang Q, Fan Y, Xu D. The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma. Front Immunol. 2022;13:971142.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Xia Y, Liu L, Long Q, Bai Q, Wang J, Xu J, et al. Decreased expression of CTR2 predicts poor prognosis of patients with clear cell renal cell carcinoma. Urol Oncol. 2016;34:5.e1–9.

    Article  PubMed  CAS  Google Scholar 

  38. Xing T, Li L, Chen Y, Ju G, Li G, Zhu X, et al. Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma. Cell Rep Med. 2023;4:101264.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Lu J, Ling X, Sun Y, Liu L, Liu L, Wang X, et al. FDX1 enhances endometriosis cell cuproptosis via G6PD-mediated redox homeostasis. Apoptosis. 2023;28:1128–40.

    Article  PubMed  CAS  Google Scholar 

  40. Wang X, Jia JH, Zhang M, Meng QS, Yan BW, Ma ZY, et al. Adrenomedullin/FOXO3 enhances sunitinib resistance in clear cell renal cell carcinoma by inhibiting FDX1 expression and cuproptosis. FASEB J. 2023;37:e23143.

    Article  PubMed  CAS  Google Scholar 

  41. Jayab NA, Abed A, Talaat IM, Hamoudi R. The molecular mechanism of NF-κB dysregulation across different subtypes of renal cell carcinoma. J Adv Res. 2025;72:501–14.

    Article  PubMed  CAS  Google Scholar 

  42. Sourbier C, Danilin S, Lindner V, Steger J, Rothhut S, Meyer N, et al. Targeting the nuclear factor-kappaB rescue pathway has promising future in human renal cell carcinoma therapy. Cancer Res. 2007;67:11668–76.

    Article  PubMed  CAS  Google Scholar 

  43. Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell. 2008;132:344–62.

    Article  PubMed  CAS  Google Scholar 

  44. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev. 2004;18:2195–224.

    Article  PubMed  CAS  Google Scholar 

  45. Orlowski RZ, Baldwin AS Jr. NF-kappaB as a therapeutic target in cancer. Trends Mol Med. 2002;8:385–9.

    Article  PubMed  CAS  Google Scholar 

  46. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-kappaB signaling. Cell Res. 2011;21:103–15.

    Article  PubMed  CAS  Google Scholar 

  47. Qin R, Liang X, Yang Y, Chen J, Huang L, Xu W, et al. Exploring cuproptosis-related molecular clusters and immunological characterization in ischemic stroke through machine learning. Heliyon. 2024;10:e36559.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Chen Y, Chen X, Wang X. Identification of a prognostic model using cuproptosis-related genes in uveal melanoma. Front Cell Dev Biol. 2022;10:973073.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by Joint Funds of the Natural Science Foundation of Tianjin(No. 25JCLMJC00320), Tianjin Natural Science Foundation Project(No. 25JCZDJC00590), Tianjin Health Science and Technology Project (No. TJWJ2024XK007), Talent Funding Program of Tianjin Institute of Urology (No. MYSRC202403), Tianjin Municipal Education Commission Scientific Research Program Project (No. 2025ZD006 and 2025ZD032) and National Training Program of Innovation and Entrepreneurship for undergraduates (No. 202510062003 and 202510062048). We would like to thank biorender for providing us with an online mapping tool. We thank Dr. Fengzhu Guo, Department of Medical Oncology, Beijing Hospital, National Center for Geriatrics, Institute of Geriatrics, Chinese Academy of Medical Sciences, for her generous donation.

Author information

Author notes

  1. These authors contributed equally: Jialu Ma, Jianqiao Li, Zhihao Bo.

Authors and Affiliations

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

    Jialu Ma, Jianqiao Li, Zhihao Bo, Shiyue Zhang, Yuankang Feng & Yong Wang

  2. Division of Medical Technology, Tianjin Medical University, Tianjin, China

    Xinyu Liu, Yihan Dong, Jiaxin Li, Shaomin Guo, Yuejing Pan, Rui Wang & Dan Yue

  3. Department of Urology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China

    Huamao Jiang

Authors
  1. Jialu Ma
    View author publications

    Search author on:PubMed Google Scholar

  2. Jianqiao Li
    View author publications

    Search author on:PubMed Google Scholar

  3. Zhihao Bo
    View author publications

    Search author on:PubMed Google Scholar

  4. Shiyue Zhang
    View author publications

    Search author on:PubMed Google Scholar

  5. Yuankang Feng
    View author publications

    Search author on:PubMed Google Scholar

  6. Xinyu Liu
    View author publications

    Search author on:PubMed Google Scholar

  7. Yihan Dong
    View author publications

    Search author on:PubMed Google Scholar

  8. Jiaxin Li
    View author publications

    Search author on:PubMed Google Scholar

  9. Shaomin Guo
    View author publications

    Search author on:PubMed Google Scholar

  10. Yuejing Pan
    View author publications

    Search author on:PubMed Google Scholar

  11. Huamao Jiang
    View author publications

    Search author on:PubMed Google Scholar

  12. Rui Wang
    View author publications

    Search author on:PubMed Google Scholar

  13. Dan Yue
    View author publications

    Search author on:PubMed Google Scholar

  14. Yong Wang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The study was designed by MJL,YW, and DY. JLM, SYZ, YKF and JQL conducted the experiments. YW, DY, RBC, and RW provided supervision for the study. Bioinformatics analysis was performed by ZHB and YHD. XYL, SPT, XYG, HMJ and JXL interpreted the results. Figures were designed by JLM, SYZ and YKF. The draft was written by JLM and ZHB. Funding was provided by YW, DY, and RBC. All authors approved the final version of the manuscript and agree to be accountable for publishing this article.

Corresponding authors

Correspondence to Rui Wang, Dan Yue or Yong Wang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, J., Li, J., Bo, Z. et al. PRR15 suppresses renal cell carcinoma progression via the NF-κB/FDX1 axis to induce cuproptosis and mitochondrial dysfunction. Oncogene 45, 840–855 (2026). https://doi.org/10.1038/s41388-026-03683-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41388-026-03683-2

Search

Advanced search

Quick links