Epigallocatechin‐3‐Gallate Mitigates Atopic Dermatitis‐Like Skin Lesions and Psychiatric Comorbidities by Reducing Oxidative Stress

Atopic dermatitis (AD), a chronic, relapsing, inflammatory skin disease often accompanied by psychiatric comorbidities like anxiety and depression, poses significant therapeutic challenges. This study aims to explore the therapeutic effects and mechanisms of dietary supplementation with epigallocatechin‐3‐gallate (EGCG) on AD skin lesions and comorbid anxiety/depressive disorders through in vivo and in vitro experiments. Macroscopical and histopathological evaluation revealed that gavage administration of EGCG (50 or 100 mg/kg) significantly improved AD skin lesions, as evidenced by the reduced dermatitis severity scores, TEWL value and blood flow perfusion, and diminished infiltration of inflammatory and mast cells ( p  < 0.05 or p  < 0.01). In EPM and OFT, EGCG‐treated mice displayed markedly decreased anxiety and depressive‐like behaviors, as manifested by the increased frequency of entries and distance traveled in the open arms and the central area, and elevated 5‐HT levels in serum/brain ( p  < 0.05 or p  < 0.01). Additionally, compared to the AD model group, EGCG administration reduced MDA content and ROS accumulation in serum/brain/skin, while enhancing GSH‐Px and CAT activity ( p  < 0.05 or p  < 0.01). Flow cytometry analysis further demonstrated that EGCG could suppress the generation of ROS in TNF‐α/IFN‐γ‐stimulated NHEK cells. Mechanistically, by virtue of in vivo, in vitro and in silico assays, the results of western blot, immunofluorescence and molecular docking discovered that EGCG could promote Nrf2 nuclear translocation and ultimately reduce oxidative stress, at least in part, by specifically targeting Keap1 to disrupt the interaction of Keap1/Nrf2 and modulation of the Keap1/Nrf2/HO‐1 axis. These aforementioned findings highlight the potential of EGCG as a promising therapeutic strategy for AD and its psychiatric comorbidities by alleviating Keap1/Nrf2/HO‐1‐mediated oxidative stress. Administration of EGCG attenuates atopic dermatitis (AD)‐like skin manifestations. EGCG ameliorates AD‐associated behavioral deficits by altering the HPA axis dysfunction and upregulating the neurotransmitters. Down‐regulation of Keap1/Nrf2/HO‐1 signaling pathway‐mediated oxidative stress might be the crucial mechanism for EGCG against AD‐like phenotype accompanied by psychological disorders.