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Cellular and Molecular Biology

Urinary proteome and metabolome uncover tumor microenvironment and cellular metabolism changes of renal clear cell carcinoma

British Journal of Cancer (2026) Cite this article

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Abstract

Background

Clear cell renal carcinoma (ccRCC) is the most frequent form of kidney tumors with high recurrence and progression rates. Early diagnosis of ccRCC could significantly improve survival rate. Liquid biopsies could capture molecular information which would not only shed more light on the signatures of the onset of ccRCC, but also discover potential biomarker for early diagnosis.

Method

We applied LC-MS to profile the urine proteome and metabolome of 314 ccRCC, 341 healthy control and 49 kidney benign disease enrolled from three cohorts. Further cell origin annotation and protein-protein correlation analysis were performed to explain the possible TME mechanistic.

Results

We revealed significant changes of extracellular matrix (ECM) organization, complement and coagulation cascades, amino acid metabolism and fatty acid metabolism in ccRCC. Cell origin annotation of cancer proteins revealed the potential role of myofibroblast cell during ECM organization. Finally, we discovered six potential urinary biomarkers, FGB,CILP, ITIH1, GUCA2B, anserine, oxindole and established models for ccRCC diagnosis with the AUC value of 0.84, 0.80 and 0.86 for protein model, metabolites model and multi-omics model in an external cohort. The protein model also showed discriminatory ability for ccRCC and benign with the AUC value of 0.75.

Conclusion

Present study provided urinary molecular changes, which could reflect TME disorder and cellular metabolism reprogramming.

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Fig. 1
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Fig. 2: Overview of urine proteome characterization of ccRCC.
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Fig. 3: Overview of urine metabolome characterization of ccRCC.
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Fig. 4: Expression of genes encoding ccRCC differential proteins in ccRCC single cells.
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Fig. 5: Urinary biomarker for ccRCC diagnosis.
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Fig. 6
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Data availability

The raw data could be downloaded from the ProteomeXchange (https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD064183).

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Funding

This work was supported by National Natural Science Foundation of China (No.82170524, 31901039), National High Level Hospital Clinical Research Funding (BJ-2022-094, BJ-2022-118, BJ-2023-202), Beijing Medical Research (No.2018-7), CAMS Innovation Fund for Medical Sciences (2021-I2M-1-016, 2022-I2M-1-020), and Biologic Medicine Information Center of China, National Scientific Data Sharing Platform for Population and Health.

Author information

Author notes

  1. These authors contributed equally: Xiaoyan Liu, Mingxin Zhang.

Authors and Affiliations

  1. Proteomics Research Center, Core Facility of Instrument, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Xiaoyan Liu, Haidan Sun, Zhengguang Guo, Feng Qi, Yuxue Zhang & Wei Sun

  2. Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China

    Mingxin Zhang & Haitao Niu

  3. Department of Urology, Peking Union Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China

    Yi Zhao & Yushi Zhang

  4. Department of Anesthesiology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, China

    Yuting Dai

  5. Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China

    Chongxu Han & Jing Chen

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  1. Xiaoyan Liu
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Contributions

LX and ZM, experiment design and text writing; ZY, DY, and CJ, multiple center sample collection and clinical information collection; HC, clinical information review and integrative analysis; SH and GZ, MS detection and helped to data analysis; QF and ZYX, sample preparation; ZYS and NH, overall study design and clinical data validation; SW, overall study design, key technical roadmap validation, and manuscript revision.

Corresponding authors

Correspondence to Yushi Zhang, Haitao Niu or Wei Sun.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Institutional Review Boardof the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences. All human subjects provided informed consent before participating in this study. The authors confirmed that all methods were performed in accordance with the relevant guidelines and regulations.

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Liu, X., Zhang, M., Zhao, Y. et al. Urinary proteome and metabolome uncover tumor microenvironment and cellular metabolism changes of renal clear cell carcinoma. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03434-w

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