Exploration of potential mechanisms and key genes associated with stress granules in immunoglobulin A nephropathy based on transcriptome and experimental validation

Background Stress granules (SGs) are involved in immunoglobulin A nephropathy (IgAN) pathogenic pathogenesis. This study aimed to identify SGs-related key genes in IgAN and explore their underlying mechanisms and therapeutic potential. Methods After IgAN modeling in rats, RNA sequencing was conducted to obtain their transcriptome data, and human SGs-related genes (SGs-RGs) were downloaded from public databases. Subsequently, differentially expressed genes (DEGs) were identified, and candidate genes were obtained by intersecting with rat SGs-RGs (converted from human SGs-RGs through homologous mapping). Key genes were finally determined through the protein-protein interaction network and the MCODE plug-in. Meanwhile, we performed in-depth analyses—including functional enrichment, drug prediction, molecular docking, and molecular dynamics simulations—on the hub genes. In addition, experimental verification of the key genes was additionally performed. Results A total of 53 candidate genes were identified. After multiple rounds of screening, Jun, Ers1, Fos, Jun, and Myc were finally determined as key genes. These genes (except Esr1) showed positive correlations (correlation > 0.30) and functional similarity (score > 0.50), and were enriched in pathways such as ribosome signaling pathway. After cross-species homologous mapping, multiple human key genes (Jun, Ers1, Fos, Jun, and Myc) were targeted by the same transcription factor or the same non-coding RNA and exhibited a shared regulatory targeting pattern. In addition, the predicted drug daidzein showed good binding activity with the corresponding proteins of key genes (docking score < -5 kcal/mol); the optimal binding system was formed by ESR1 and daidzein, while the most stable and rigid binding system was formed by PTGS2 and daidzein. Moreover, these bioinformatics findings were further verified experimental assays. Conclusion Jun, Ers1, Fos, Jun, and Myc were potential key genes associated with SGs in IgAN. Daidzein might target them to exert therapeutic effects, providing a reference for revealing SGs' role in IgAN.