Integrative Proteomic and Phosphoproteomic Analysis Reveals Altered Vesicle Transport in Systemic Lupus Erythematosus.

Vesicle transport genes (VTGs) are involved in the pathogenesis and progression of systemic lupus erythematosus (SLE). A comprehensive multi-omics analysis is crucial to elucidate their molecular alterations and identify potential biomarkers and therapeutic targets. However, studies investigating global alterations of VTGs in SLE remain limited. In this study, we aimed to investigate the relationship between VTGs alterations and SLE progression. We integrated proteomic and phosphoproteomic data from 130 SLE patients and 90 healthy controls (HC). This was combined with transcriptomic profiles from 1,461 SLE cases and 198 HC. Focusing on VTGs, our multi-omics analysis identified key phosphorylation events, stage-specific kinases, and transcription factor-target interactions. We then constructed signaling pathway networks for both the stable and active phases of SLE. Proteomic analysis revealed altered expression across vesicle subclasses and marked dysregulation of critical processes such as organelle transport and autophagy in SLE. Phosphoproteomic profiling identified multiple aberrant phosphorylation sites and highlighted ITSN2 S889 as a potential hub phosphorylation site. Integrated analysis defined Clusters 4, 6, and 9 as early-altered molecules, and Clusters 1, 3, and 8 as progression-altered molecules. It also identified CLTC and its phosphorylated form T105 as candidate hub molecules. Multi-omics integration confirmed significant upregulation of HP and SAMD9 at both mRNA and protein levels, and implicated STAT1 and RELA as potential regulatory transcription factors (TFs). Based on their functional roles, kinases such as PKACB, SYK, PDGFRA, LCK, PKCA, PKCD, TBK1, AKT1, and DLK were implicated in the underlying pathogenic mechanism, whereas TAK1, AKT2, AKT3, and PITSLRE were associated with disease progression. A comprehensive signaling map capturing stage-dependent network alterations in SLE was constructed. This study contributes to a thorough understanding of the connection between alterations in VTGs and the development of SLE. It provides an integrated molecular map of VTGs dysregulation in SLE, suggesting potential opportunities for the development of diagnostic biomarkers and therapeutic interventions. [Image: see text] The online version contains supplementary material available at 10.1186/s12014-026-09599-z.