Cholesterol and Stearamide Mediate Lymphocyte Apoptosis and Cytokine Secretion in Systemic Lupus Erythematosus

Alterations in serum metabolite composition have been increasingly associated with systemic lupus erythematosus (SLE), yet the direct effects of these metabolites on immune cell function remain poorly defined. This study aimed to identify peripheral blood metabolites associated with SLE and evaluate their impact on apoptosis and cytokine secretion in lymphocytes derived from SLE patients. We performed a two-sample Mendelian randomization (MR) analysis to investigate the relationship between 565 serum metabolites and SLE, using the inverse-variance weighted model as the primary analytical approach. Significant findings were cross-validated using previously published untargeted metabolomics data based on liquid chromatography-mass spectrometry (LC-MS). In functional experiments, lymphocytes isolated from SLE patients were stimulated with target metabolites, followed by assessment of apoptosis and cytokine secretion. MR analysis identified 28 metabolites significantly associated with SLE. Of these, cholesterol (OR = 1.462, 95% CI: 1.100-1.940, P = 0.008) and stearamide (OR = 0.125, 95% CI: 0.020-0.660, P = 0.014) were validated through LC-MS and found to be elevated in SLE patients. Receiver operating characteristic analysis demonstrated strong diagnostic performance (AUC = 0.999 for cholesterol; AUC = 1.000 for stearamide). Functionally, both metabolites induced increased apoptosis and elevated secretion of TNF-α, IFN-γ, and TGF-β1 in SLE lymphocytes. In summary, our integrated approach combining genetic association, metabolite profiling, and functional assays reveals that cholesterol may contribute to immune dysregulation in SLE. Although stearamide showed a negative association with SLE risk in MR analysis, its in vitro effects mirrored those of cholesterol, suggesting a complex and context-dependent role. These findings underscore the importance of lipid metabolism in SLE and support further mechanistic and clinical investigation of its immunological impact.