Proteomic and Crotonylomic Integration of a Self-Established IgA Nephropathy Cohort Reveals Dysregulated Secretory Proteins and Immune Cell Regulators

Background Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide, with 20–40% of patients progressing to end-stage renal disease. However, the molecular mechanisms linking peripheral immune dysregulation to local renal injury-particularly the regulatory patterns and post-translational modifications (PTMs) of secreted proteins-remain largely unexplored. Methods Using a self-established IgAN clinical cohort, we integrated renal tissue proteomics, peripheral blood mononuclear cell (PBMC) crotonylomics, transcriptomic datasets, and immune-secreted protein annotations from the Human Protein Atlas. Differential expression, protein-protein interaction network mapping, hub protein screening, functional enrichment, and transcription factor prediction were performed to delineate regulatory networks. Candidate therapeutic agents were explored through drug repositioning using DSigDB and Enrichr platforms. Results Compared with healthy controls, 92 differentially expressed secreted proteins and 36 crotonylation-modified secreted proteins were identified in the peripheral immune cells of patients with IgAN. PPI network and module analyses revealed a dual-layer “secreted protein-crotonylation-immune regulation” network, in which FGA, FGG, and S100A9 were identified as core hub proteins. Four upstream transcription factors (STAT1, PML, STAT5B, and MYH11) were further predicted, ,implicating them as potential key regulators of secretory protein dysregulation in IgAN. In addition, drug repositioning analysis using the Drug Signatures Database (DSigDB) and Enrichr platforms identified thapsigargin as a potential candidate drug capable of modulating the secreted protein network in IgAN immune cells. Conclusions In this study, we present the first integrated proteomic and crotonylomic analysis to systematically characterize the expression profiles and crotonylation patterns of secretory proteins from peripheral immune cells in IgAN. This analysis identifies key hub proteins and transcriptional regulators, providing novel molecular insights into the pathogenesis of IgAN. Our findings lay a theoretical foundation for the development of targeted therapeutic strategies and underscore the potential of cross-omics integration in elucidating ‘immune-organ’ interactions.