Therapeutic Effect of Arsenic Trioxide in Human Lupus Nephritis: Results from Network Pharmacology and Ex Vivo Studies

Background: The renal response to standard treatments of lupus nephritis (LN) often remains suboptimal. Preliminary studies showed efficacy of low-dose arsenic trioxide (ATO) in active systemic lupus erythematosus (SLE), but the mechanisms of action are poorly understood. Methods: Three machine learning approaches and network pharmacology were applied to screen out the predictive targets of differentially expressed genes (DEGs) from human SLE and LN peripheral blood mononuclear cells (PBMCs) and kidney biopsy datasets. Functional enrichment analysis was conducted. The relationship between characteristic genes and inflammatory cell infiltration was further analyzed and validated in ex-vivo experiments. Results: Twelve predictive intersected DEGs in SLE patients were selected. Functional enrichment analysis showed a strong association between IL-17 signaling pathway and ATO in SLE (p =1.67E-18). Amongst these DEGs, five immunoregulatory genes were further identified by machine learning models, with MMP9 showing the highest AUC (0.942) by ROC curve analysis. Similar results were validated in kidney biopsy and PBMCs from different LN datasets. Our in vitro experiments showed that ATO could downregulate MMP9 and IL17 expression in PBMCs isolated from LN patients (n=5). Ex-vivo studies suggested that ATO may induce apoptosis and inhibit proliferation of CpG-stimulated CD19+ B cells from LN patients. Conclusion: ATO shows promising effects on B lymphocyte inhibition via downregulation of MMP9, and hence has good potential to be repurposed for the treatment of SLE and LN. Funding: Other NIH Support - Wai Im Charitable Foundation, Chan Sui Kau Family Benefits and Charitable Foundation, So Ka Wing and Lee Sau Ying Charitable FoundationFig1Fig2