Revival of AHR Agonist for the Treatment of Atopic Dermatitis: Tapinarof

Abstract

The aryl hydrocarbon receptor (AHR) system is a sensitive sensor for small-molecule, xenobiotic chemicals of exogenous and endogenous origin, including dioxins, phytochemicals, microbial bioproducts, and tryptophan photoproducts. Once activated, the AHR signal strengthens skin barrier functions and accelerates epidermal terminal differentiation by upregulating filaggrin expression. Coal tar and glyteer are crude mixtures of compounds that have been used for inflammatory skin diseases such as type 2 cytokine-dominant atopic dermatitis (AD). Both of them are antioxidative AHR ligands and simultaneously activate the nuclear factor erythroid 2–related factor-2 (NRF2) transcription factor, which is a master switch of antioxidative enzymes that neutralizes oxidative stress. Type 2 cytokines activate signal transducer and activator of transcription 6 (STAT6) and inhibit filaggrin expression. Coal tar and glyteer inhibit this type 2 cytokine-mediated STAT6 activation by decreasing the type 2 cytokine-induced oxidative stress. However, patients hesitate to use them on a daily basis because of their bad smell and black color. A single compound, tapinarof, is an antioxidative AHR agonist and also activates the NRF2 system. Recent clinical trials have revealed that topical tapinarof is efficacious for the treatment of AD. Its adverse events, including headache and folliculitis, are mild and tolerable. Topical tapinarof may be a valuable substitute for coal tar and glyteer. Further clinical trials of its use, including for pediatric AD, are warranted.