Diagnosis, Prognosis, and Drug Target Discovery for Chronic Widespread Pain: A Large Proteogenomic Study

Li Chen^{1

2}, Eoin Kelleher³, Ruogu Meng⁴, Duanke Liu⁵, Yuchen Guo¹, Yunhe Wang⁶, Yaqing Gao⁶, Zhe Huang⁶, Zhu Liang⁷, Shuai Yuan^{8

9}, Chao Zeng¹⁰, Jun Ma², Yanhui Dong², Anushka Irani^{1

11}, Guanghua Lei¹⁰, Junqing Xie^{1

12}, Daniel Prieto-Alhambra^{1

13}

Affiliations

¹ Centre for Statistics in Medicine and NIHR Biomedical Research Centre Oxford, NDORMS, University of Oxford, Oxford, OX3 7LD, UK.
² Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, 100191, China.
³ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
⁴ National Institute of Health Data Science, Peking University, Beijing, 100191, China.
⁵ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
⁶ Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
⁷ Nuffield Department of Medicine, Target Discovery Institute, Center for Medicines Discovery, University of Oxford, Oxford, OX3 7FZ, UK.
⁸ Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, PA, 19104, USA.
⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 171 77, Sweden.
¹⁰ Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410013, China.
¹¹ Division of Rheumatology, Mayo Clinic Florida, Florida, 32224, USA.
¹² The Queen's College, University of Oxford, Oxford, OX1 4AW, UK.
¹³ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, 3015 GD, The Netherlands.

PMID: 41025730
DOI: 10.1002/advs.202507691

Diagnosis, Prognosis, and Drug Target Discovery for Chronic Widespread Pain: A Large Proteogenomic Study

Li Chen et al. Adv Sci (Weinh). 2025.

. 2025 Sep 30:e07691.

doi: 10.1002/advs.202507691. Online ahead of print.

Authors

Affiliations

¹ Centre for Statistics in Medicine and NIHR Biomedical Research Centre Oxford, NDORMS, University of Oxford, Oxford, OX3 7LD, UK.
² Institute of Child and Adolescent Health, School of Public Health, Peking University, Beijing, 100191, China.
³ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
⁴ National Institute of Health Data Science, Peking University, Beijing, 100191, China.
⁵ Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
⁶ Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
⁷ Nuffield Department of Medicine, Target Discovery Institute, Center for Medicines Discovery, University of Oxford, Oxford, OX3 7FZ, UK.
⁸ Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, PA, 19104, USA.
⁹ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, 171 77, Sweden.
¹⁰ Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410013, China.
¹¹ Division of Rheumatology, Mayo Clinic Florida, Florida, 32224, USA.
¹² The Queen's College, University of Oxford, Oxford, OX1 4AW, UK.
¹³ Department of Medical Informatics, Erasmus University Medical Center, Rotterdam, 3015 GD, The Netherlands.

PMID: 41025730
DOI: 10.1002/advs.202507691

Abstract

Chronic widespread pain (CWP) remains challenging due to its heterogeneous causes and complex mechanisms. A total of 2920 plasma proteins are analyzed from 29,254 UK Biobank participants. A total of 256 proteins are identified as cross-sectionally correlated with CWP. A simple (top 10 proteins) and comprehensive (all significant proteins) proteomic-based score (ProtS) is created for CWP diagnosis, both outperforming and improving the existing clinical score (area under the curve, AUC: 0.801, 0.723, and 0.791 alone, and 0.856 and 0.880 in combination). In addition, the protein score predicted 13-years risk of pain-related traits over the body, including pain onset, progression, and intensity; Moreover, it has stronger associations with nociplastic pain and fibromyalgia compared to nociceptive and neuropathic pain, implying a unique protein signature of different pain mechanisms. Finally, among 434 candidate proteins prioritized in the observational analysis, 18 are corroborated with causal relevance by Mendelian randomization, and importantly, four (CA14, DPEP1, LGALS3, and TNF) showed potential as novel drug targets repurposed for treating CWP.

Keywords: biomarker; drug‐repurposing; nociplastic pain; proteomic; wide spread pain.

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Diagnosis, Prognosis, and Drug Target Discovery for Chronic Widespread Pain: A Large Proteogenomic Study

Affiliations

Diagnosis, Prognosis, and Drug Target Discovery for Chronic Widespread Pain: A Large Proteogenomic Study

Authors

Affiliations

Abstract

References