Liquid-liquid phase separation-related genes in the immune microenvironment and diagnosis of focal segmental glomerulosclerosis and minimal change disease

Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are major causes of primary nephrotic syndrome. However, the mechanisms of liquid-liquid phase separation (LLPS)-related genes in the development of FSGS and MCD remain unclear. We retrieved the Gene Expression Omnibus (GEO) database for the expression profiles of FSGS and MCD and identified the differentially expressed genes (DEGs) related to LLPS. Algorithms including Vector Machine-Recursive Feature Elimination (SVM-RFE) and Random Forest (RF) were adopted to identify the candidate genes. Functional enrichment analysis, nomogram, immune infiltration analysis, the receiver operating characteristic <b>(</b>ROC) curve analysis, and external validation were performed. The research identified 59 and 40 DEGs related to LLPS for FSGS and MCD, respectively. Two candidate genes [PDS5 cohesin-associated factor A (PDS5A) and exosome component 2 (EXOSC2)] were obtained for FSGS, and three candidate genes [PDS5A, KH RNA-binding domain-containing signal transduction-associated 1 (KHDRBS1), and JunD proto-oncogene (JUND)] were obtained for MCD. Both the nomogram and ROC analysis indicated that the candidate genes had good predictive performance. For FSGS, the area under the curve (AUC) values of PDS5A and EXOSC2 were 0.994 and 0.806, respectively. For MCD, the AUC values of PDS5A, KHDRBS1, and JUND were 1, 0.896, and 0.958, respectively. Immune infiltration analysis revealed that FSGS patients had higher levels of naive B cells while MCD patients had higher levels of M2 macrophages and resting mast cells.PDS5A may represent a potential diagnostic biomarker, and targeting its aberrant phase separation may offer a therapeutic strategy for podocytopathies.