Integrative proteo-metabolomic analysis in rheumatoid arthritis reveals potential therapeutic targets: Harnessing Mendelian randomization.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder that severely compromises joint structure and function. Understanding its molecular mechanisms is essential for identifying reliable biomarkers and potential therapeutic targets. In this study, we performed an integrative proteome- and metabolome-wide Mendelian randomization (MR) analysis to explore the causal relationships between circulating plasma proteins, metabolites, and RA risk. The primary MR analysis identified 32 proteins and 13 metabolites significantly associated with RA. These associations were supported by multiple sensitivity analyses, confirming the robustness and reliability of the findings. Reverse MR analyses indicated that these proteins and metabolites are more likely to contribute causally to RA pathogenesis, rather than representing downstream effects of the disease. Colocalization analyses further strengthened these results by revealing shared genetic variants between RA and nine proteins and one metabolite, highlighting their causal potential. To refine causal inference, MR-based Bayesian model averaging (MR-BMA) prioritized BRD2, p38, and NF-κB1 as the top candidate proteins with the highest likelihood of contributing to RA. Functional enrichment analyses implicated several key immune-related pathways, including natural killer (NK) cell-mediated cytotoxicity, the p38 MAPK cascade, and NF-κB signaling that contribute to RA pathogenesis. External validation using an independent RA cohort from the UK Biobank confirmed the associations of the core proteins. Furthermore, gene and protein expression analyses in a training dataset demonstrated significant differential expression between RA patients and healthy controls, further supporting the functional relevance of these targets. Collectively, our findings provide novel insights into the molecular landscape of RA, identify promising biomarkers and therapeutic targets, and establish a foundation for future translational and clinical research.