Integrated Multiomics Profiling Reveals Membrane‐Associated Signaling Alterations Associated With Disease Activity in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by pervasive immune dysregulation, yet membrane-associated molecular alterations in immune cells remain incompletely defined. Here, we performed integrated proteomic and phosphoproteomic profiling of peripheral blood mononuclear cells (PBMCs) from a self-established cohort of 130 SLE patients across disease stages and 90 healthy controls, with individual samples pooled into 36 samples for LC-MS/MS analysis, complemented by publicly available transcriptomic data from 1461 SLE patients. Focusing on membrane-associated proteins, we identified alterations in protein abundance and phosphorylation involving cytoskeletal organization, cell adhesion, and membrane trafficking, with the RHO GTPase cycle consistently enriched in both omic layers. Dynamic multisite phosphorylation of FLNA and increased abundance of FLNB and FNBP1 were observed. Clustering revealed distinct disease-stage-associated patterns involving integrin proteins in SLE in remission (SLE_R) and cytoskeletal and mechanotransduction components in active SLE (SLE_A). OAS3 and IFIT5 showed concordant transcript-protein changes, while interferon- and NF-κB-related transcriptional programs were implicated. Computational kinase analysis identified disease-stage-associated predicted activity patterns involving PKC, MAPKs, CDKs, and CaM-Ks. Together, these findings provide a multiomics view of membrane-associated molecular alterations associated with disease activity in SLE.