Revealing Shared Therapeutic Targets and Intervention Methods in B Cells for IgA Nephropathy and Membranous Nephropathy: A Study Integrating scRNA-seq and Computational Pharmacology

The clinical outcomes of immune-mediated glomerular diseases such as IgA nephropathy (IgAN) and membranous nephropathy (MN) are heterogeneous. The persistence and recurrence of diseases are significantly influenced by Pathogenic Memory B cells (MBCs) and long-lived plasma cells (LLPCs), though the molecular mechanisms they share remain unclear.

We combined single-cell RNA sequencing (scRNA-seq) with computational pharmacology methods. The scRNA-seq data from human kidney biopsies of IgAN and MN were sourced from the Gene Expression Omnibus (GEO) database. For each disease, B cell clusters were identified and analyzed for differences in gene expression. The genes that were differentially expressed in both diseases were intersected to discover common targets. To investigate the biological importance of the shared targets, functional enrichment analysis was conducted, incorporating KEGG and protein-protein interaction (PPI) network analysis. Chuanlianzi (Melia toosendan) bioactive compounds were extracted from the TCMSP database and evaluated for drug-likeness (DL ≥ 0.18) and oral bioavailability (OB≥30%). The binding affinity and pharmacokinetic profiles of these compounds with the target protein were assessed using molecular docking and ADMET prediction.

The overlap of differentially expressed genes in B cells from IgAN and MN revealed several shared targets, with HSPE1 chosen for additional study. Further KEGG pathway enrichment analysis on the disease-specific differential genes identified two common pathways between IgAN and MN: FoxO and MAPK signaling. Analysis of protein-protein interaction networks for genes in these shared pathways revealed that HSPE1, which encodes the mitochondrial chaperone HSP10, was positioned downstream in both pathways, highlighting its importance as a key gene due to its vital role in preserving mitochondrial balance and enhancing cell survival. From these findings, we suggest that HSP10 aids in the survival of pathogenic memory B cells (MBCs) and long-lived plasma cells (LLPCs). Molecular docking showed the binding affinities of bioactive compounds from Chuanlianzi to HSP10, and ADMET prediction offered insights into their pharmacokinetic and safety profiles.

This research suggests that HSPE1/HSP10 could be a new shared therapeutic target for IgAN and MN, possibly supporting the persistence of resistant B cell groups. Moreover, stigmasterol and especially quercetin are suggested as strong inhibitors of HSP10 with favorable ADMET characteristics.