Chronic widespread pain (CWP) remains challenging due to its heterogenous causes and complex mechanisms. We analysed 2,923 plasma proteins from 29,254 UK Biobank participants. We first identified 811 proteins correlated with the presence of CWP cross-sectionally. We then created a sparse (top 10 proteins) and intricate (all significant proteins) proteomic-based score (ProtS) for CWP, both outperforming and improving the traditional clinical score (AUC: 0.82 and 0.88 vs 0.81 individually, and 0.87 and 0.92 in combination). Prospectively, the ProtS was associated with increased risks of a spectrum of pain traits, including dimensions from pain onset, progression and intensity, up to 13-years of follow-up; More importantly, we identified distinct proteomic signatures for nociplastic pain compared to nociceptive and neuropathic pain. For the individual proteins, carbonic anhydrase 14 (CA14) and leptin appeared as promising casual CWP biomarkers as triangulated by Mendelian randomisation and colocalization analyses. Lastly, our drug-repurposing analysis identified ten potential candidates for CWP therapies, calling for further research including randomised controlled trials. Although no CA14 agonists are currently available, CA14 remains a promising target, warranting further efforts to explore its role in pain modulation.

The authors have declared no competing interest.

DPA and JX received partial support from the Oxford National Institute for Health and care Research (NIHR) Biomedical Research Centre. The present study was supported by China National Natural Science Foundation of China (Grant 82103865 and 82373593 to Yanhui Dong) and Natural Science Foundation of Beijing (Grant 7222244 to Yanhui Dong), Peking University Talent Introduction Program Project (BMU2023YJ011 to Yanhui Dong).

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https://www.ukbiobank.ac.uk

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