Plasma Proteomics Identifies TAOK3 as a Potential Biomarker of Rheumatoid Arthritis Activity and a Novel Therapeutic Target

Objective Bone destruction associated with active rheumatoid arthritis (RA) remains a major therapeutic challenge, with a lack of reliable molecular markers reflecting bone injury. This study aims to identify novel biomarkers linked to bone destruction in active RA through proteomic analysis, providing new strategies for precise monitoring and targeted therapy. Methods Data‐independent acquisition (DIA) mass spectrometry was used for proteomic quantification and bioinformatic analysis on plasma samples from 160 RA patients and 40 healthy controls. Key proteins associated with bone destruction were screened by integrating Sharp scores with synovial single‐cell RNA sequencing data, and subsequently validated in two independent cohorts (N₁ = 50, N₂ = 10) using ELISA and multiplex immunohistochemistry. Functional studies were conducted using fibroblast‐like synoviocytes (FLSs) in vitro and a collagen‐induced arthritis (CIA) mouse model in vivo. Results A total of 4,998 plasma proteins were identified, with 506 showing significant differential expression between active and remitted RA. TAOK3 levels were positively associated with Sharp scores and markedly elevated in active RA patients. Combining TAOK3 with CRP improved diagnostic accuracy for active RA (AUC = 0.915). High TAOK3 expression was also associated with increased relapse frequency. Functional studies showed that TAOK3 knockdown suppressed the tumor‐like phenotype of FLSs and downregulated MMP1/2/3 and CTSK, while TAOK3 overexpression promoted pannus cell–mediated bone erosion, mitigated by TAOK3‐targeted inhibitor. In vivo, its inhibition showed therapeutic effects in CIA mice. Conclusion TAOK3 serves as a potential biomarker for bone destruction in active RA and a therapeutic target for precision monitoring and intervention.