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Despite advances in targeted therapies, significant interindividual variability in treatment response and a lack of precise predictive tools limit the achievement of treat\u2010to\u2010target goals. This review aims to establish a signaling pathway\u2013biomarker\u2010targeted therapy coupling paradigm to address unmet clinical needs in precision rheumatology. We systematically reviewed the literature on core pathogenic cascades (JAK\/STAT, MAPK, phosphoinositide 4\u2010kinase\u2013AKT\/mechanistic target of rapamycin, spleen tyrosine kinase, Wnt, and Notch) and their crosstalk in RA. We analyzed the direct coupling between pathway dysregulation and specific biomarkers and evaluated emerging therapeutic strategies. We identified a direct mapping between aberrant pathways and biomarkers (eg, interleukin\u20106 or C\u2010reactive protein for JAK\/STAT, matrix metalloproteinase 3 for MAPK). Critically, we argue that the failure of most biomarker\u2010driven trials stems not from the biomarkers themselves but from treating RA as a single entity rather than a spectrum of pathway\u2010dominant endotypes. Current clinical translation is hindered by heterogeneity and a disconnect between bench research and bedside application. Emerging strategies, including highly selective kinase inhibitors, proteolysis\u2010targeting chimeras, and nanoparticle\u2010mediated delivery systems, show promise in overcoming these bottlenecks. Bridging the gap between dysregulated signaling pathways and validated biomarkers is essential for advancing precision medicine in RA. A roadmap for pathway\u2010guided individualized treatment is proposed.<\/jats:p>","DOI":"10.1002\/acr2.90136","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:59:12Z","timestamp":1787561952000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Signaling Pathway\u2013Biomarker Coupling for Precision Therapy in Rheumatoid Arthritis: Mechanistic Insights, Translational Bottlenecks, and Emerging Strategies"],"prefix":"10.1002","volume":"8","author":[{"given":"Shijie","family":"Meng","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Affiliated Hospital of Nantong University  Nantong China"},{"name":"Affiliated Hospital of Nantong University, Medical School of Nantong University  Nantong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic 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