Molecular Signatures of Nuclear Protein Alterations in Systemic Lupus Erythematosus across Disease Stages

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune dysregulation and the production of autoantibodies targeting nuclear components; yet, the molecular mechanisms linking nuclear protein alterations to disease activity remain poorly defined. Here, we performed integrative proteomic and phosphoproteomic analyses of peripheral blood mononuclear cells from 90 healthy individuals and 130 SLE patients, complemented by transcriptomic profiling of 1,461 SLE patients. Our multiomics analysis revealed progressive dysregulation of nuclear proteins, particularly those involved in RNA processing and immune regulation, with distinct subsets associated with remission and active disease states. Phosphoproteomic profiling uncovered dynamic phosphorylation changes, including reduced multisite phosphorylation of FKBP15 and aberrant activation of kinases such as CDK and CK2. Transcriptome-proteome integration highlighted persistent interferon signaling and inflammatory gene expression, while transcription factor (TF) analysis indicated dysregulation of STAT1 and IRF family members. Network analysis identified central hub proteins, such as NPM1 and PARP1, that bridge post-translational modifications with global transcriptional alterations. Collectively, these findings delineate a multilayered regulatory network connecting protein abundance, phosphorylation dynamics, and TF activity, thereby providing mechanistic insights into SLE pathogenesis and suggesting potential biomarkers and therapeutic targets for disease modulation.