Comprehensive Metabolomic Profiling of Skin Lesions from Psoriasis Patients Reveals Disease Signatures

Psoriasis is a chronic skin disease caused by dysregulated immune system. Although inflammation plays a vital role, the precise chemical changes within the skin remain unclear and metabolomic profiling of skin lesions has been limited by small sample sizes and narrow metabolite coverage. In this study, we performed wide-targeted metabolomics of skin samples from 30 psoriasis patients and 30 healthy controls to identify differential metabolites that may drive the disease. We identified 707 differential metabolites across 21 classes, including amino acids, fatty acids, organic acids, nucleotides, and others. Among them, two metabolites, UDP-N-acetyl-3-O-(1-carboxyvinyl)-D-glucosamine and ethylparaben, were strongly linked to psoriasis. Further analysis revealed that these changes were driven by specific differentiated keratinocytes and involved metabolomic enzyme-encoding genes related to nucleotide and pyrimidine metabolism pathways. To identify metabolites associated with disease severity, we grouped patients by PASI and BSA scores and identified 27 metabolites that increased as the disease worsened via Mfuzz clustering analysis. Among them, citrate and L-tyrosine significantly exacerbated disease by increasing skin thickness and inflammation after validation in vivo. Our findings provide a comprehensive map of metabolic changes in psoriatic skin and highlight citrate and L-tyrosine as potential indicators for disease severity and promising targets for future treatments.