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Objectives Monocytes play versatile roles in host defense, inflammation regulation and immune activation and are key effector cells in human systemic lupus erythematosus (SLE). Overproduction of cytokines, self-antigen presentation and amplification of tissue inflammation represent outcomes of transcriptional rewiring within the inflammatory milieu of the disease.This study aimed to delineate the altered transcriptome of monocytes in SLE, investigate how epitranscriptomic RNA editing affects their function, and assess whether transcriptional perturbations are linked to changes in chromatin organization.Methods Monocytes from 8 SLE patients (SLEDAI >8) and 5 age- and sex-matched healthy controls were isolated from PBMCs by Ficoll centrifugation and CD14+ magnetic bead selection. Single-end 75-bp mRNA sequencing was performed, and differential expression was analyzed using edgeR (p-value < 0.05, fold change >1.5), followed by pathway enrichment analysis with clusterProfiler. A trained immunity signature was constructed from publicly available data and compared with our experiment. A-to-I RNA editing events were profiled with JACUSA2, retaining high-confidence sites (score > 2.5) present in REDIportal and significant differences in editing frequency (Wilcoxon rank-sum test, p < 0.05). Domains of Coordinated Expression (DCEs), defined as genomic regions of consecutive chromosomal bin with gene expression correlation above healthy average, were estimated to examine whether altered gene expression patterns correspond to chromatin organization changes.Results A total of 1,368 differentially expressed genes (DEGs) were identified, including 761 upregulated and 607 downregulated in SLE monocytes. Upregulated DEGs were enriched in pathways related to biotic stimulus response, cell chemotaxis, T-cell differentiation, RNA polymerase function, and IL-17 signaling. Our genes showed correlation with trained immunity. Interestingly ADARB1, a key regulator of RNA editing, was upregulated, and SLE monocytes exhibited significantly increased A-to-I editing frequencies, particularly in immune-related genes such as ARPC2, IL17RA, TLR2, and OSCAR. Most editing sites were in the UTR3 and intronic regions. DCE analysis revealed extensive redistribution of chromatin co-expression activity, indicating rearrangement of transcriptional coordination.Conclusions SLE monocytes exhibit widespread transcriptional changes. These findings highlight RNA editing as an additional player of immune-related epigenetic memory of monocytes while chromatin disorganization amplifies transcriptional dysregulation. Collectively, these alterations integrate inflammatory cues and enhance the autoimmune identity characteristic of the disease.