Epalrestat repurposing for psoriasis: Targeting AKR1B10 to modulate the metabolic-immune axis via restoring retinol metabolism and suppressing IL-17 signaling.

Abstract

BACKGROUND: Psoriasis is a chronic inflammatory disease often accompanied by metabolic syndrome. The function of AKR1B10 in the "metabolism-immune" interplay remains unclear. This study aimed to identify the role of AKR1B10 in pathogenesis and evaluate its inhibitor, Epalrestat, for psoriasis treatment via drug repurposing. METHODS: Integrating GEO transcriptomic data, we screened for key metabolic signature genes. An imiquimod (IMQ)-induced murine psoriasis model was established to evaluate the efficacy and safety of intragastric and topical epalrestat, as assessed by PASI scores, histopathology, spleen index and body weight monitoring. Furthermore, RNA sequencing, functional enrichment analysis, protein-protein interaction analysis, immunofluorescence and RT-qPCR were performed to explore the underlying mechanisms. RESULTS: AKR1B10 was identified as a key differentially expressed gene positively correlating with activated DCs, neutrophils and Th17 cells (AUC = 0.970). In vivo, Epalrestat significantly ameliorated skin lesions, reduced PASI scores, and exhibited a safety profile superior to methotrexate(MTX). Mechanistically, Epalrestat treatment upregulated retinol metabolism while markedly suppressing the IL-17 signaling pathway. CONCLUSIONS: Epalrestat alleviates skin inflammation by inhibiting AKR1B10 activity, thereby restoring retinol homeostasis. The subsequent suppression of the IL-17 signaling axis is more likely a downstream consequence of improved metabolic status and a remodeled inflammatory microenvironment, rather than a direct effect. These findings support Epalrestat as a potential therapeutic agent for psoriasis that concurrently modulates metabolic and inflammatory pathways.