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A total of 2920 plasma proteins are analyzed from 29,254 UK Biobank participants. A total of 256 proteins are identified as cross\u2010sectionally correlated with CWP. A simple (top 10 proteins) and comprehensive (all significant proteins) proteomic\u2010based 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\u2010years risk of pain\u2010related 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.<\/jats:p>","DOI":"10.1002\/advs.202507691","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T12:36:54Z","timestamp":1759235814000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Diagnosis, Prognosis, and Drug Target Discovery for Chronic Widespread Pain: A Large Proteogenomic Study"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8607-8997","authenticated-orcid":false,"given":"Li","family":"Chen","sequence":"first","affiliation":[{"name":"Centre for Statistics in Medicine and NIHR Biomedical Research Centre Oxford NDORMS University of Oxford Oxford OX3 7LD 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