Identification of hub ferroptosis-related genes and immune infiltration in lupus nephritis using bioinformatics

Abstract

Lupus nephritis (LN) is one of the most severe and more common organ manifestations of the autoimmune disease, systemic lupus erythematosus. Ferroptosis, a novel type of programmed cell death, so far its role in LN remains uncertain. In the present study, we explored the role of ferroptosis in LN and its relationship with the immune response. The GSE112943 LN dataset was downloaded from the Gene Expression Omnibus database. Ferroptosis-Related Genes (FRGs) that drive, suppress or mark ferroptosis were retrieved from the public FerrDb database. The gene expression matrix of the GSE112943 dataset was analyzed with the "limma" package in R to obtain differentially expressed genes (DEGs) between LN and healthy samples. Subsequently, the crossover genes between DEGs and FRGs were identified as differentially expressed ferroptosis-related genes (DE-FRGs). Protein-protein interaction (PPI) network analysis, visualization, and identification of hub lupus nephritis ferroptosis-related genes (LN-FRGs) were performed with STRING and Cytoscape, while their Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were determined with the clusterProfiler package. Immune cell infiltration was calculated with CIBERSORT. The relationship between hub LN-FRGs and immune-infiltrated cells in LN was determined by Pearson correlation. A total of 96 DE-FRGs and 8 hub LN-FRGs (KRAS, PIK3CA, EGFR, MAPK14, SRC, MAPK3, VEGFA, and ATM) were identified. GO and KEGG functional classification indicated these genes enrichment in apoptotic process, programmed cell death, autophagy-animal, FoxO signaling pathway, relaxin signaling pathway, and VEGF signaling pathway. Infiltration matrix analysis of immune cells showed abundant Monocytes and M0/M1/M2 macrophages in LN kidney tissues. Correlation analysis revealed 8 hub LN-FRGs associated with immune-infiltrated cells in LN. In summary, overproduction of ROS and abnormal infiltration of immune cells would be implicated in the LN caused by ferroptosis. 8 hub lupus nephritis ferroptosis-related genes (LN-FRGs) which might be good biomarkers of ferroptosis in LN were identified in this study. These findings point to the immune response playing an important role in LN caused by ferroptosis via mutual regulation between hub LN-FRGs and immune-infiltrated cells.