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The present study aimed to investigate the potential of epimedin A to ameliorate DNFB-induced allergic contact dermatitis (CD) and reveal its potential underlying mechanisms of action, emphasizing its role in modulating NF-κB/NLRP3, Nrf2/HO-1 pathways, and inflammation. Seven-week-old BALB/c mice received epimedin A orally for 11 days at doses of 5, 10, or 20 mg/kg/day, starting from the seventh day of DNFB-inducing CD. Epimedin A dose-dependently ameliorated DNFB-induced CD, as revealed by the repression of the mice's scratching behavior, dermatitis score, ear thickness and weight, and ear tissue's histopathological changes, and area percent of collagen fibers induced by DNFB. These potentials were due to the NF-κB/NLRP3 pathway suppression and the Nrf2 pathway enhancement, as demonstrated by the reduction of NF-κB, NLRP3, ASC, caspase-1, and 8 mRNA expression, and NF-κBp65, IL-1β, MDA levels, and NF-κBp65 binding activity, along with the enhancement of the Nrf2, HO-1, IκB-α, GSH levels, SOD activity, and Nrf2 binding activity. Besides, it suppressed ear tissues' NLRP3 and caspase-8 induced pyroptosis by suppressing the ear tissues' caspase-1, 8, GSDMD upregulation, and LDH activity. Additionally, it repressed the local inflammatory reaction of ear tissue, as evidenced by the reduction of the elevated inflammatory cytokines (IL-1β, IL-6, Il-4, TNF-α, and IFN-γ), the serum level of t-IgE, DNFB s-IgE, s-IgE/t-IgE ratio, and the abrogation of the ear tissues histopathological changes. Epimedin A is a novel, hopeful, natural therapeutic agent for CD by modulating NF-κB/NLRP3, Nrf2 pathways, and inflammation. [ABSTRACT FROM AUTHOR]