Integrated Proteomic and Phosphoproteomic Profiling Reveals Dysregulated Inflammatory Signaling Networks in Rheumatoid Arthritis.

Aberrant protein phosphorylation orchestrates sustained inflammatory immune signaling in rheumatoid arthritis (RA), yet the coordinated remodeling of proteomic and phosphoproteomic landscapes in peripheral blood mononuclear cells (PBMCs) remains poorly resolved via system-level multi-omics integration. In this article, we integrated quantitative proteomics, phosphoproteomics, and public transcriptomic datasets from PBMCs of RA patients and healthy controls to unravel multilayered molecular circuits driving RA autoimmune pathology. Differentially expressed proteins were enriched in perturbed fatty acid metabolism and RNA processing pathways, while phosphoproteome quantification uncovered a striking inverse correlation between protein phosphorylation stoichiometry and total protein abundance. Network topological analyses prioritized actin beta (ACTB) and HSP90AA1 as core phosphoprotein hubs controlling cytoskeletal dynamics and mRNA splicing. Cross-omics regulatory integration identified HDAC1, together with transcription factors CBFB, PML, and STAT1, as master mediators bridging phospho-signaling cascades to inflammatory transcriptional programs. Kinome activity inference further revealed disease-reconfigured signaling networks centered on protein kinase C alpha and protein kinase C delta in RA immune cells. Collectively, this integrative multiomics study delineates a phosphorylation-inflammation pathogenic axis in RA, pinpoints druggable hub proteins and kinases as promising therapeutic candidates, and provides a comprehensive systems-level framework to decipher immune metabolic and signaling dysregulation in chronic autoimmune inflammatory disorders.