ObjectiveTo identify potential diagnostic markers of lupus nephritis (LN) based on bioinformatics and machine learning and to explore the significance of immune cell infiltration in this pathology.MethodsSeven LN gene expression datasets were downloaded from the GEO database, and the larger sample size was used as the training group to obtain differential genes (DEGs) between LN and healthy controls, and to perform gene function, disease ontology (DO), and gene set enrichment analyses (GSEA). Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE), were applied to identify candidate biomarkers. The diagnostic value of LN diagnostic gene biomarkers was further evaluated in the area under the ROC curve observed in the validation dataset. CIBERSORT was used to analyze 22 immune cell fractions from LN patients and to analyze their correlation with diagnostic markers.ResultsThirty and twenty-one DEGs were screened in kidney tissue and peripheral blood, respectively. Both of which covered macrophages and interferons. The disease enrichment analysis of DEGs in kidney tissues showed that they were mainly involved in immune and renal diseases, and in peripheral blood it was mainly enriched in cardiovascular system, bone marrow, and oral cavity. The machine learning algorithm combined with external dataset validation revealed that C1QA(AUC = 0.741), C1QB(AUC = 0.758), MX1(AUC = 0.865), RORC(AUC = 0.911), CD177(AUC = 0.855), DEFA4(AUC= 0.843)and HERC5(AUC = 0.880) had high diagnostic value and could be used as diagnostic biomarkers of LN. Compared to controls, pathways such as cell adhesion molecule cam, and systemic lupus erythematosus were activated in kidney tissues; cell cycle, cytoplasmic DNA sensing pathways, NOD-like receptor signaling pathways, proteasome, and RIG-1-like receptors were activated in peripheral blood. Immune cell infiltration analysis showed that diagnostic markers in kidney tissue were associated with T cells CD8 and Dendritic cells resting, and in blood were associated with T cells CD4 memory resting, suggesting that CD4 T cells, CD8 T cells and dendritic cells are closely related to the development and progression of LN.ConclusionC1QA, C1QB, MX1, RORC, CD177, DEFA4 and HERC5 could be used as new candidate molecular markers for LN. It may provide new insights into the diagnosis and molecular treatment of LN in the future.