Identification of cellular senescence-associated hub genes and molecular targeting mechanisms of thalidomide in lupus nephritis (LN).

Abstract

Systemic lupus erythematosus (SLE), a chronic autoimmune disease, progresses to lupus nephritis (LN) in 50-60% of patients, driving end-stage renal disease (ESRD). Identifying LN-associated cellular senescence hub genes and drug targets is critical for elucidating pathogenesis and advancing targeted therapies. Integrated transcriptomic data from LN patients (GSE61635, GSE121239; n = 441) were analyzed to identify differentially expressed genes (DEGs) using the limma package (|log2FC| > 0.5 and FDR < 0.05). Cellular senescence-associated differentially expressed genes (CS-DEGs) were further filtered through hypergeometric testing using the CellAge database. Functional enrichment analysis performed with ClusterProfiler and DOSE packages revealed significantly enriched pathways based on GO, KEGG, and GSEA terms (FDR < 0.05). A protein-protein interaction (PPI) network was constructed using STRING data and visualized in Cytoscape to prioritize hub genes. The drug-target interactions of these hub genes were subsequently validated via molecular docking and dynamics simulations using CB-Dock2. A total of 1,098 DEGs (555 upregulated, 543 downregulated) were identified. Functional enrichment revealed 60 CS-DEGs significantly enriched in viral response, myeloid differentiation, and antiviral defense (FDR < 0.05). KEGG analysis highlighted their roles in lipid metabolism/atherosclerosis, NOD-like receptor signaling, and Influenza A. PPI-based topological and modular analyses prioritized CCL2, MYD88, STAT1, JUN, JAK2, and FOS as hub genes, further refined to CCL2, JUN, JAK2, and FOS via ceRNA network. Drug screening identified thalidomide as a potential candidate, with strong binding affinity to all targets, particularly CCL2 (ΔG = -92.7 kcal/mol, forming three stable hydrogen bonds). This study revealed the role of CS-DEGs in viral response, immune regulation, and lipid metabolism in LN. Network analysis prioritized CCL2, JUN, JAK2, and FOS as hub genes. Thalidomide exhibited strong binding to these targets, notably CCL2 (ΔG = -92.7 kcal/mol), suggesting therapeutic potential via CCL2-mediated mechanisms. These findings advance LN pathogenesis understanding and precision-targeted therapies.