Integrated analysis identifies dysregulated secretory proteins and crotonylation profiles associated with immune...

Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide, with 20%-40% of patients progressing to end-stage renal disease. However, the relationship between peripheral immune alterations and local renal injury, particularly with respect to the abundance patterns and post-translational modification signals of secretory proteins, remains incompletely characterized.

This study included 48 samples, consisting of renal tissue samples from 7 IgAN patients and 10 controls, and peripheral blood mononuclear cells (PBMCs) from 6 patients with IgAN and 25 controls. Renal tissue and PBMC samples were analyzed by proteomic and crotonylation profiling, respectively. These datasets represent cohort-level feature integration rather than paired multi-omics correlation analyses performed within the same individuals. Immune secretory protein annotations from the Human Protein Atlas supported downstream interpretation. Differential abundance analysis, protein-protein interaction (PPI) network analysis, functional enrichment, transcription factor (TF) prediction, and compound enrichment analysis using the DSigDB and Enrichr platforms were performed to explore molecular features and database-derived compounds associated with IgAN.

Compared with the corresponding control groups, 92 differentially abundant secreted proteins and 36 secretory proteins with differential protein-abundance-normalized Kcr signals were identified in IgAN patients. PPI network analysis prioritized FGA, FGB, A2M, APOA1, C3, HP, SERPINA1, APOB, FGG, and TF as exploratory hub candidates, while STAT1, PML, STAT5B, and MYH11 were computationally predicted as candidate upstream TFs. Compound enrichment analysis identified thapsigargin as a database-derived, hypothesis-generating compound related to the secretory protein network in IgAN.

This study provides an integrative characterization of secretory protein abundance and crotonylation patterns in IgA nephropathy. The findings suggest candidate hub proteins and upstream TFs potentially associated with immune dysregulation in IgAN. Despite the limited sample size, these results offer exploratory molecular insights and provide a basis for future mechanistic and experimental studies.

Secretory proteins may contribute to immune dysregulation and renal injury in immunoglobulin A nephropathy (IgAN), but their abundance patterns and lysine crotonylation (Kcr)-related features remain incompletely characterized. This study integrated renal tissue proteomics, peripheral blood mononuclear cell crotonylomics, public transcriptomics, and Human Protein Atlas annotations at the feature level across independent cohorts. Descriptive fold-change screening yielded 92 HPA-annotated secretory proteins in renal tissue and 36 secretory proteins containing 120 protein-abundance-normalized Kcr sites in peripheral blood mononuclear cells. Network analysis prioritized ten exploratory hub candidates, while STAT1, PML, STAT5B, and MYH11 were computationally prioritized as candidate upstream transcription factors. DSigDB/Enrichr analysis further highlighted thapsigargin as a database-derived enrichment signal for hypothesis generation. These findings provide an exploratory molecular resource for investigating secretory protein abundance and Kcr-related patterns in IgAN. Because the datasets were unpaired and the proteomic and crotonylomic samples were pooled within groups, the results do not establish participant-level cross-tissue relationships, causal regulation, validated biomarkers, or therapeutic efficacy. Larger individual-level cohorts and functional studies are required for validation.