Signaling Pathway-Biomarker Coupling for Precision Therapy in Rheumatoid Arthritis: Mechanistic Insights, Translational Bottlenecks, and Emerging Strategies.

Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease. Despite advances in targeted therapies, significant interindividual variability in treatment response and a lack of precise predictive tools limit the achievement of treat-to-target goals. This review aims to establish a signaling pathway-biomarker-targeted 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-kinase-AKT/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-6 or C-reactive protein for JAK/STAT, matrix metalloproteinase 3 for MAPK). Critically, we argue that the failure of most biomarker-driven trials stems not from the biomarkers themselves but from treating RA as a single entity rather than a spectrum of pathway-dominant 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-targeting chimeras, and nanoparticle-mediated 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-guided individualized treatment is proposed.