Abstract

Background Although immune dysregulation is implicated in both autoimmune diseases and cancer, comparative pathogenesis and immune response mechanisms between systemic lupus erythematosus (SLE) and colorectal cancer (CRC) remain elusive. This study identifies common molecular biomarkers and pathogenic pathways shared between SLE and CRC via multi-omics analysis. Methods Integrated datasets including SLE ( GSE61635 , GSE50772 , GSE142016 ) and CRC cohorts ( GSE39582 , GSE17536 , E-MTAB-8107, COAD, READ), were analyzed. Differential expression analysis identified shared genes, and machine learning screened four hub prognostic genes. A risk model based on these genes was constructed to evaluate SLE screening and CRC prognosis. Multi-omics approaches explored mutational profiles, immune infiltration, drug sensitivity, and signaling pathways. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), staining were performed to confirmed the expression levels of the hub genes. The impact of DNASE1L3 knockdown in the human monocyte cell line THP-1 on phagocytosis of apoptotic intestinal epithelial cell line NCM460 was evaluated using RT-qPCR and flow cytometry. Results We identified 58 shared differentially expressed genes (DEGs) between SLE and CRC, enriched in apoptosis, oxidative phosphorylation, and immune infiltration. Machine learning highlighted four hub genes ( DNASE1L3 , PTPN14 , SELENBP1 , ECRG4 ), forming a robust predictive model for SLE occurrence and CRC prognosis. Shared immune infiltration patterns and small-molecule drug candidates were observed. Single-cell and spatial transcriptomic analyses revealed DNASE1L3 predominantly in myeloid cells. Cellular experiments revealed that reduced DNASE1L3 levels significantly compromised macrophage efferocytosis of apoptotic cells, accompanied by a decrease in M2 macrophage proportion, an increase in M1 macrophage proportion, diminished LOX enzyme activity, and elevated levels of interleukin-1 β