Serum Lipid-Proteome Profiling Unveils Metabolic-Immune Dysregulation in IgAN

Background: IgA nephropathy (IgAN), the most common glomerulonephritis, is driven by galactose-deficient IgA1 (Gd-IgA1) deposition, leading to progressive kidney injury. Limited therapies and unclear mechanisms of immune-metabolic crosstalk prompted this multi-omics study to unravel lipid-protein interactions in IgAN pathogenesis. Methods: IgAN patients (biopsy-confirmed, Oxford MEST-C) and healthy controls underwent serum lipidomics (HPLC-QTRAP 6500+) and proteomics (LC-MS/MS). Bioinformatics included limma-based differential analysis, pathway enrichment (Wikipathway/Reactome), and lipid-protein networks. Results: 1.Lipid Dysregulation: ↑TGs (P<0.001), DGs, NeuAcHex2Cer; ↓LPAs (P<0.01), FFAs. Hyperlipidemia (↑TG, ↓HDL) and renal dysfunction (↓eGFR, ↓Alb). 2.Proteome Alterations: Upregulated: VEGFA-VEGFR2 (*FDR=0.002*) – endothelial leakage. Downregulated: Galactose metabolism (*FDR=0.01*), NRF2. ↑GALK1/↓PGM1 implicates dysregulated galactose disposal. 3.Correlations: TGs: Linked to neutrophils (ρ=0.62), blood pressure, urine SG. LPAs: Associated with eGFR (ρ=0.71), serum Alb. Neutrophil Suppression: ↓HEXB/PRCP (P<0.05); TG/LPA-correlated proteins enriched in neutrophil degranulation (*FDR=0.005*). Conclusion: Systemic TG-LPA imbalance impairs neutrophil-mediated IC clearance, while VEGFA-VEGFR2 exacerbates endothelial leakage. Serum TG/LPA ratios and HEXB/PRCP are potential biomarkers for IC persistence. Targeting lipid profiles (e.g., TG-lowering) may mitigate IgAN progression. Funding: Government Support – Non-U.S.Figure 1. Lipidomics and proteomics analyses of the systemic microenvironment of IgAN based on serum profiles of IgAN and HC Figure 2. Differentially expressed serum TGs and LPAs functionally converge on neutrophil function