Entadamide A-β-D-glucopyranoside attenuates psoriatic dermatitis by restoring keratinocyte homeostasis and suppressing neutrophil extracellular traps.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Entada phaseoloides (L.) Merr. is a well-established traditional Chinese medicine (TCM) and Dai Medicine historically utilized for treating inflammatory skin conditions like dermatitis, as well as hemorrhoids and arthritis, leveraging its wound-healing, analgesic, antipyretic, and detoxifying properties. Entadamide A-β-D-glucopyranoside (EA), a major bioactive constituent in the seeds of Entada phaseoloides (L.) Merr., has demonstrated anti-inflammatory potential while its efficacy and possible mechanism against psoriasis remain unknown. AIM OF THE STUDY: To investigate the therapeutic potential and underlying mechanisms of EA against psoriatic dermatitis. MATERIALS AND METHODS: The efficacy of EA was evaluated using histopathological changes analysis, immunohistochemistry, immunofluorescence, immunoblotting, molecular docking and RT-qPCR based on the in vitro models, an ex vivo model and in vivo imiquimod (IMQ)-induced mouse psoriasis model. RESULTS: EA treatment significantly alleviated IMQ-induced psoriasiform dermatitis, reducing epidermal hyperplasia, scaling, immune cell infiltration, and PASI scores. Further, EA suppressed keratinocyte hyperproliferation (as marked by keratin 16, keratin 17 and PCNA) and restored differentiation markers (as marked by keratin 1). EA potently inhibited pro-inflammatory cytokine release including interleukin-36 (IL-36) cytokines, IL-1β, IL-6, tumor necrosis factor (TNF)-α, HMGB1 and neutrophil extracellular trap (NET) formation in psoriatic lesions. Mechanistically, molecular docking indicated that EA exhibits moderate binding affinity for both IL-36R and P2X7R, inhibiting downstream NLRP3 inflammasome activation. CONCLUSION: EA alleviates psoriasiform dermatitis by restoring keratinocyte homeostasis, suppressing immune cell infiltration and NET formation, suggesting its potential as a therapeutic agent derived from TCM.