Palmitoylation Dynamics in Systemic Lupus Erythematosus: Multi‐Omics Insights and Potential Therapeutic Implications

ABSTRACT Objective Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by immune dysregulation. The role of palmitoylation in regulating immune responses and its contribution to SLE pathogenesis remains insufficiently understood. Methods We conducted a multi‐omics analysis using the GSE61635 dataset to identify differentially expressed genes (DEGs) in SLE. Palmitoylation‐related genes (PRGs) were identified through differential expression analysis, weighted gene co‐expression network analysis (WGCNA), and machine learning models. Single‐cell RNA sequencing (scRNA‐seq) was used to assess immune cell dynamics, and Mendelian randomization (MR) was employed to explore causal relationships between metabolites and SLE. Results We identified 3946 DEGs and 13 key PRGs associated with palmitoylation in SLE. Four hub genes (ACSL1, ZDHHC12, GPX1, and DDHD2) were highlighted as potential biomarkers. Functional enrichment analysis revealed that these genes are involved in fatty acid metabolism and immune signaling. scRNA‐seq analysis showed increased palmitoylation activity in neutrophils and cytotoxic T lymphocytes (CTLs) in SLE. MR analysis identified four phospholipids containing palmitic acid as causally linked to SLE. Conclusion This study identifies ACSL1 and ZDHHC12 as potential therapeutic targets for modulating palmitoylation and immune responses in SLE. Further research is required to validate these findings and explore their clinical implications for SLE treatment.