Immunometabolic dysregulation is increasingly recognized as a pivotal contributor to systemic lupus erythematosus (SLE). This study aims to identify novel circulating biomarkers within plasma exosomes that link fatty acid metabolic rewiring to SLE pathogenesis. Plasma exosomes were isolated from patients with active SLE, inactive SLE, rheumatoid arthritis (RA) and healthy controls by ultracentrifugation. The proteomic and metabolomic profiles were characterized using liquid chromatography-mass spectrometry (LC-MS). Exosomal fibroblast activation protein (FAP) expression was validated by nanoflow cytometry, and fatty acid metabolites were confirmed by targeted metabolomics. Proteomic profiling revealed a marked enrichment of FAP in plasma exosomes from SLE patients, with the highest levels in active SLE. Nanoflow cytometry further validated that plasma exosomal FAP was specifically increased in SLE but not RA. Besides, metabolomics identified a characteristic fatty acid signature in SLE plasma exosomes, featuring increased saturated (palmitic acid, etc) and ω-6 polyunsaturated fatty acids (PUFAs) (arachidonic acid (AA), etc), alongside decreased ω-3 PUFAs (α-linolenic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), etc). Moreover, the AA/DHA and total ω-6/ω-3 ratios were significantly elevated, while the EPA/AA ratio was reduced in active SLE. Integrated omics analysis revealed the close relationship of exosomal FAP with fatty acid metabolism. Notably, exosomal FAP levels correlated positively with SLEDAI-2000 score and the pro-inflammatory fatty acid profiles (AA, total ω-6, AA/DHA ratio), but negatively with the anti-inflammatory profiles (DHA, EPA, total ω-3, EPA/AA ratio). We identify plasma exosomal FAP as a novel biomarker linking fatty acid metabolic dysregulation to SLE.
Zhang et al. (Mon,) studied this question.