Integrative multi-omics profiling of a self-established cohort reveals metabolic reprogramming networks in rheumatoid...

Rheumatoid arthritis (RA) is a chronic, autoimmune disorder characterized by systemic inflammation and metabolic dysregulation. However, the mechanisms underlying metabolic reprogramming in RA peripheral blood mononuclear cells (PBMCs) remain poorly understood. Therefore, we integrated proteomic and phosphoproteomic data from PBMCs of 96 RA patients and 90 healthy controls (HCs) with transcriptomic data from 113 RA patients and 54 HCs to identify differential proteins, key phosphorylation sites, kinase activity alterations, and transcription factor-target interactions. Potential therapeutic modulators were predicted using the Drug Signature Database (DSigDB) and the Therapeutic Target Database (TTD). Proteomic analysis revealed upregulation of proteins involved in RNA metabolism, oxidative phosphorylation, and other metabolic pathways, while phosphoproteomics identified 27 metabolism-associated phosphorylation sites, including Actin Beta (ACTB) Ser33 (upregulated) and Nucleophosmin 1 (NPM1) Ser10 (downregulated). Cyclin-dependent kinase (CDK) family members may be associated with metabolic reprogramming by modulating RNA-related pathways. Integrative analysis highlighted Nuclear Factor Kappa B Subunit 1 (NFKB1), Nuclear Factor Kappa B Subunit 2 (NFKB2), Signal Transducer and Activator of Transcription 1 (STAT1), Signal Transducer and Activator of Transcription 2 (STAT2), and Core-Binding Factor Subunit Beta (CBFB) as potential upstream transcriptional regulators. Several compounds, including flavopiridol hydrochloride, serine, diclofenac, and carbamazepine, may serve as potential modulators of RA-associated metabolic remodeling. Unlike previous studies limited to single-omics data, our integrative analysis of proteomics, phosphoproteomics, and transcriptomics systematically delineates metabolic regulatory networks in RA immune cells and identifies novel candidate targets, thereby offering new mechanistic insights and potential directions for therapeutic intervention.