Multi-omics analysis suggests a potential role of the complement-coagulation axis in hypercoagulability of membranous nephropathy.

Membranous nephropathy (MN), a leading cause of nephrotic syndrome, is associated with hypercoagulability and an increased risk of thromboembolic events; however, the relationship between coagulation-related alterations and the immune microenvironment remains incompletely understood. In this study, microarray datasets (GSE73953 and GSE140713) and single-cell RNA sequencing data (GSE233275) were obtained from the Gene Expression Omnibus (GEO), and a broad set of coagulation-related genes was retrieved from GeneCards. Differentially expressed coagulation-related genes (DECGs) between peripheral blood mononuclear cells (PBMCs) from MN patients and healthy controls were identified. Functional enrichment and protein-protein interaction (PPI) network analyses were performed, and candidate hub genes were prioritized using multiple topological algorithms. Single-cell RNA sequencing data were analyzed exploratorily to evaluate the cellular distribution and disease-associated expression patterns of hub genes across immune cell populations. Receiver operating characteristic (ROC) curves were used to assess the apparent discriminatory performance of hub genes between MN and healthy control PBMC samples in an exploratory manner. Immune cell infiltration was estimated using CIBERSORTx, and correlations between hub genes, immune cell subsets, and coagulation-related genes were evaluated. In addition, glomerular proteomics data from PXD054062 were independently analyzed to explore potential links between systemic PBMC alterations and the local renal microenvironment. A total of 413 DECGs were identified, and five hub genes (CCL5, CYBB, C3AR1, JUN, and TIMP1) were prioritized. Among them, C3AR1 was closely associated with monocyte-related signatures and was positively correlated with the coagulation-related gene F2R. Glomerular proteomics analysis indicated enrichment of complement- and coagulation cascade-related proteins in MN samples, suggesting that local complement-related alterations may coexist with procoagulant or thrombo-inflammatory features in the kidney. Taken together, this study proposes a hypothesis-driven model in which C3a/C3AR1-related monocyte activation and F2R/PAR-1 expression may be interrelated with procoagulant and inflammatory features in MN. This model remains exploratory and requires direct validation in patient samples and mechanistic experiments. These findings may help generate testable hypotheses for future studies on MN-associated hypercoagulability.