The Therapeutic Aryl Hydrocarbon Receptor-Modulating Agent Tapinarof Restores Skin Barrier Dysfunction in a Mite Antigen-Induced Murine Model of Atopic Dermatitis

Atopic dermatitis (AD) is characterized by pruritus and epidermal barrier dysfunction. Tapinarof, a therapeutic aryl hydrocarbon receptor (AHR)-modulating agent, is clinically effective in AD, but its mechanisms in allergen-driven models remain unclear. We evaluated tapinarof in a Dermatophagoides farinae (Df)-induced murine model of AD, focusing on AHR-mediated barrier restoration. AD-like dermatitis was induced in female NC/Nga mice, followed by daily topical tapinarof or betamethasone for four days. Disease severity, transepidermal water loss (TEWL), histopathology, and gene/protein expression were assessed. Tapinarof significantly reduced dermatitis scores and TEWL and, unlike betamethasone, preserved epidermal architecture without suppressing ear swelling. Tapinarof upregulated the AHR-responsive genes Cyp1a1 and Nqo1 and induced Ovol1, an epidermal differentiation-associated transcription factor, with increased CYP1A1, NRF2, NQO1, and OVOL1 protein expression. Tapinarof markedly increased filaggrin (FLG)- and loricrin (LOR)-positive areas in lesional skin compared with vehicle (FLG: 11.3% vs. 3.1%; LOR: 18.9% vs. 3.9%; both p < 0.05), restoring FLG to a level comparable to the no-treatment control, while LOR significantly exceeded it. These findings indicate that tapinarof may restore skin barrier function in allergen-induced AD via AHR-NRF2 and AHR-OVOL1 signaling, supporting its potential as a steroid-sparing topical therapy for long-term AD management.