Immunoglobulin A nephropathy (IgAN) is a common primary glomerular disease linked to ferroptosis. We aimed to identify key ferroptosis-related genes in IgAN and clarify their mechanism.
Methods
Based on the data from GEO, FerrDb, Genecards, and previous publications, differential expression analysis, Machine learning (LASSO and SVM-RFE), and Weighted correlation network Analysis were exploited to screen the ferroptosis-related genes in IgAN. Furthermore, immune infiltration analysis, GSEA, and receiver operator characteristic curve were performed to identify the key genes and evaluate their diagnostic ability. A TGF-β1-induced HK-2 cell model of fibrosis with oe-DUSP1 transfection and treatment with the p38 MAPK activator U-46619 was used to validate the findings.
Results
We identified 23 ferroptosis-related differential expressed genes in IgAN, enriched in ECM-receptor interaction, focal adhesion, and allograft rejection. Four genes (CDO1, NR4A1, JUN, DUSP1) exhibited promising diagnostic value in IgAN (AUC > 0.90). NR4A1 and DUSP1 were down-regulated in IgAN and correlated with immune cell infiltration like Eosinophil, immature B cell, and activated B cell. DUSP1 overexpression inactivated p38 MAPK, increased Nrf2 and ferroptosis markers (GPX4 and SLC7A11), decreased Fe2+ and fibrosis. U-46619 addition had no effects on DUSP1, but reversed above alterations.
Conclusions
NR4A1 and DUSP1 are key diagnostic markers in IgAN, with DUSP1 modulating fibrosis via p38 MAPK/Nrf2-mediated ferroptosis.
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