Unsaturated Fatty Acid Metabolic Reprogramming in Psoriatic Skin Drives Inflammation and Predicts Response to Biologic Therapy.

Purpose: Psoriasis is frequently associated with dyslipidemia, yet the role of specific unsaturated fatty acid (UFA) metabolic pathways in disease pathogenesis and treatment response remains poorly understood. This study aimed to characterize the landscape of UFA metabolic reprogramming in psoriasis and evaluate its clinical relevance for predicting response to biologic therapy. Patients and Methods: We performed an integrated multi-omics analysis incorporating transcriptomic data from human psoriatic lesions, single-cell RNA sequencing, and lipidomic profiling. Gene set variation analysis (GSVA) was used to evaluate UFA pathway activity. Logistic regression and LASSO were employed for biomarker selection and predictive modeling. Results: We identified eight significantly dysregulated UFA metabolic pathways in psoriatic lesions, six of which were associated with key pathogenic processes in psoriasis. All pathways were reversibly modulated by biologic agents targeting TNF-α, IL-12/23, and IL-17A. We derived a three-gene biomarker signature (PLA2G4D, PLA2G4A, and FADS2) that robustly predicts response to IL-12/23 inhibition prior to treatment initiation (AUC = 0.902). Single-cell RNA sequencing revealed keratinocytes as the primary cellular contributors to UFA metabolism and identified an expanded PLA2G4D-high keratinocyte subpopulation in psoriatic skin, which was associated with the accumulation of Lysophosphatidylcholine (LysoPC) and Lysophosphatidylethanolamine (LysoPE). Conclusion: Our findings elucidate the pathway-level metabolic basis of psoriasis inflammation and provide a clinically applicable tool for predicting response to biologic therapy. The results highlight the importance of UFA metabolic reprogramming in psoriatic pathogenesis and offer new avenues for treatment personalization.