Effects of Arsenic Trioxide in MRL/lpr Mice: Disease-Context Support from Human Transcriptomic and DNA Methylation...

To evaluate the therapeutic effects of arsenic trioxide (ATO) in lupus-prone mice and to determine whether SOCS1/JAK2/STAT3/IL-17A-related inflammatory regulation is relevant to human systemic lupus erythematosus (SLE) using public transcriptomic and DNA methylation datasets. Two in vivo experiments were performed using MRL/lpr mice. The first assessed the effects of ATO on hepatorenal injury and inflammatory gene expression. The second further evaluated these findings using C57BL/6 controls and MRL/lpr mice treated with ATO, 5-Azacytidine (5-Aza), or their combination. Serum biomarkers, histopathology, and the mRNA expression of the SOCS1/JAK2/STAT3 axis were analyzed. Network pharmacology was used to predict potential ATO-related targets and pathways in SLE. WGCNA was performed using the GSE4588 human CD4⁺ T-cell transcriptomic dataset to identify SLE-associated co-expression modules. Disease-context support was assessed using the GSE65391 whole-blood transcriptomic dataset. SOCS1 promoter-associated methylation was further evaluated using the GSE82218 PBMC DNA methylation dataset. ATO improved lupus-like manifestations in MRL/lpr mice, reduced anti-dsDNA antibodies, IgG, urinary protein, and hepatorenal injury markers, restored complement C3, and alleviated renal and hepatic inflammation. At the molecular level, ATO treatment was associated with reduced DNMT1 expression, increased SOCS1 expression, and decreased JAK2, STAT3, and IL-17A transcription. Network pharmacology highlighted Th17 cell differentiation as a candidate ATO-related pathway in SLE. WGCNA of the GSE4588 human CD4⁺ T-cell transcriptomic dataset identified SLE-associated co-expression modules and hub genes. STRING/Cytoscape analysis further identified hub genes including CD44, TLR4, THBS1, and TET2, suggesting disease-associated immune and inflammatory network remodeling in SLE CD4⁺ T cells. In GSE65391, JAK2 and STAT3 expression and JAK/STAT-related signatures were increased in SLE. In the GSE82218 DNA methylation cohort, SOCS1 promoter-associated CpG sites showed site-specific hypermethylation in SLE. ATO ameliorates lupus-like immune and hepatorenal injury in MRL/lpr mice, accompanied by DNMT1/SOCS1-related transcriptional changes and reduced JAK2/STAT3/IL-17A-related inflammatory transcription. Public human transcriptomic and DNA methylation data support the disease relevance of this regulatory context.