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  • Perspective
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A standardized framework for circulating blood proteomics

Nature Genetics volume 57, pages 2371–2380 (2025)Cite this article

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Abstract

The circulating blood proteome holds immense potential for biomarker discovery and understanding disease mechanisms. Notable advances in mass spectrometry and affinity-based technologies have been made, but data integration across studies and platforms is hindered by the absence of unified analytical standards. This limitation impedes comprehensive exploration of human biology across diverse phenotypes and cohorts as well as the translation of findings into clinical applications. The disparities between datasets, stemming from a combination of factors related to differences in sample collection, pre-analytical handling, measurement methods and instrumentation, further complicate data integration. In this Perspective, we outline key challenges in blood-based proteomics and propose actionable strategies. Central to our recommendations are high-quality, technology-agnostic reference samples, which can bridge disparate datasets and enable robust cross-study comparisons. By fostering interconnected investigations across proteomic technologies, blood sample collections, clinical phenotypes and different populations, these references will accelerate the field and its translation.

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Fig. 1: Workflows for analyzing the circulating blood proteome.
Fig. 2: Potential of reference samples to allow comparability between diverse circulating blood proteome datasets.
Fig. 3: A preliminary standardization framework for reference materials in circulation blood proteomic studies.

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Acknowledgements

We are thankful for financial support from the following grants: the National Natural Science Foundation of China (Key Joint Research Program, grant U24A20476); the National Key R&D Program of China (grants 2022YFF0608403 and 2021YFA1301600); the ‘Pioneer’ and ‘Leading Goose’ R&D Program of Zhejiang (grant 2024SSYS0035); NIH grants P30ES017885-11-S1 and U24CA271037 (G.S.O.), as well as the German Ministry of Education and Research (BMBF), as part of the National Research Node ‘Mass spectrometry in Systems Medicine (MSCoresys)’ under grant agreement 031L0220 to M.R. We thank π-Hub for supports to this work (grant number 2024-SP-008). Y.P.-R. thanks European Molecular Biology Laboratory core funding, Wellcome grants (208391/Z/17/Z and 223745/Z/21/Z) and the BBSRC grant ‘DIA-Exchange’ (BB/X001911/1). J.M.S. acknowledges the Knut and Alice Wallenberg Foundation for funding the Human Protein Atlas. We thank S. R. Piersma and T. V. Pham for their comments. We thank the HUPO community for advancing the field of proteomics.

Author information

Authors and Affiliations

  1. Affiliated Hangzhou First People’s Hospital, State Key Laboratory of Medical Proteomics, School of Medicine, Westlake University, Hangzhou, China

    Xue Cai, Yi Zhu & Tiannan Guo

  2. Westlake Laboratory of Life Sciences and Biomedicine, Westlake Center for Intelligent Proteomics, Hangzhou, China

    Xue Cai, Yi Zhu & Tiannan Guo

  3. Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou, China

    Xue Cai, Yi Zhu & Tiannan Guo

  4. ions.bio GmbH, Martinsried, Germany

    Philipp E. Geyer

  5. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK

    Yasset Perez-Riverol

  6. Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

    Gilbert S. Omenn

  7. Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Gilbert S. Omenn

  8. Human Genetics, University of Michigan, Ann Arbor, MI, USA

    Gilbert S. Omenn

  9. Environmental Health, University of Michigan, Ann Arbor, MI, USA

    Gilbert S. Omenn

  10. Center for Advanced Measurement Science, National Institute of Metrology, Beijing, China

    Lianhua Dong, Yang Zhao, Xinhua Dai & Xiang Fang

  11. Advanced Genomics Unit, Center for Research and Advanced Studies, Irapuato, Mexico

    Robert Winkler

  12. Alkahest, Inc., San Carlos, CA, USA

    Sara Ahadi

  13. Absea Biotechnology GmbH, Berlin, Germany

    Philip Lössl

  14. State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences—Beijing (PHOENIX Center), Beijing Institute of Lifeomics, Beijing, China

    Xiaobo Yu & Cheng Chang

  15. Department of Biochemistry, Charité – Universitätsmedizin Berlin, Berlin, Germany

    Markus Ralser & Ziyue Wang

  16. OncoProteomics Laboratory, Department of Medical Oncology, Amsterdam UMC, location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands

    Connie R. Jimenez

  17. Cancer Center Amsterdam, Amsterdam, the Netherlands

    Connie R. Jimenez

  18. Institute of Chemistry, Academia Sinica, Taipei, Taiwan

    Yu-Ju Chen

  19. Pilot Laboratory, MOE Frontier Science Centre for Precision Oncology, Centre for Precision Medicine Research and Training, Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, China

    Terence C. W. Poon

  20. Evosep Biosystems, Odense, Denmark

    Nicolai Bache

  21. State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Human Phenome Institute and Shanghai Cancer Center, Fudan University, Shanghai, China

    Leming Shi

  22. International Human Phenome Institutes (Shanghai), Shanghai, China

    Leming Shi

  23. SciLifeLab, Department of Protein Science, KTH Royal Institute of Technology, Solna, Sweden

    Jochen M. Schwenk

  24. Advanced Clinical Biosystems Research Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA

    Jennifer E. Van Eyk

  25. Department of Functional Genomics, Interfaculty Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

    Uwe Völker

  26. German Centre for Cardiovascular Research (DZHK), partner site Greifswald, Greifswald, Germany

    Uwe Völker

Authors
  1. Xue Cai
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  2. Philipp E. Geyer
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  3. Yasset Perez-Riverol
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  4. Gilbert S. Omenn
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  5. Lianhua Dong
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  6. Robert Winkler
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  7. Sara Ahadi
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  8. Philip Lössl
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  9. Xiaobo Yu
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  10. Cheng Chang
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  11. Markus Ralser
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  12. Connie R. Jimenez
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  13. Yang Zhao
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  14. Yu-Ju Chen
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  15. Terence C. W. Poon
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  16. Nicolai Bache
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  17. Leming Shi
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  18. Xinhua Dai
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  19. Ziyue Wang
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  20. Yi Zhu
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  21. Xiang Fang
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  22. Jochen M. Schwenk
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  23. Jennifer E. Van Eyk
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  24. Uwe Völker
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  25. Tiannan Guo
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Contributions

T.G., U.V., J.E.V.E. and J.M.S. conceived the idea and lead the discussion with all coauthors; X.C. and T.G. summarized the discussion and drafted the first draft. X.C., P.E.G., Y.P.-R., G.S.O., L.D., R.W., S.A., P.L., X.Y., C.C., M.R., C.R.J., Y. Zhao., Y.-J.C., T.C.W.P., N.B., L.S., X.D., Z.W., Y. Zhu., X.F., J.M.S., J.E.V.E., U.V. and T.G. revised the manuscript.

Corresponding authors

Correspondence to Jochen M. Schwenk, Jennifer E. Van Eyk, Uwe Völker or Tiannan Guo.

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Competing interests

T.G. and Y. Zhu are shareholders of Westlake Omics. P.E.G. is an employee of Ions Biotechnologies. P.L. is an employee of Absea Biotechnology. N.B. is employee of Evosep. M.R. is the founder and shareholder of Eliptica. S.A. was a full-time employee of Alkahest, a Grifols company. J.M.S. is a scientific advisor for ABC Labs. The other authors do not have conflicts of interest related to this work.

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Nature Genetics thanks Benjamin Sun and Christopher Whelan for their contribution to the peer review of this work.

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Cai, X., Geyer, P.E., Perez-Riverol, Y. et al. A standardized framework for circulating blood proteomics. Nat Genet 57, 2371–2380 (2025). https://doi.org/10.1038/s41588-025-02319-7

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