Tapinarof as a Therapeutic Aryl Hydrocarbon Receptor‐Modulating Agent in the Treatment of Atopic Dermatitis

Atopic dermatitis (AD) is a chronic inflammatory dermatitis underpinned by Type 2 inflammation driven by cytokines such as IL-4 and IL-13. It is characterized by skin barrier dysfunction, Th2 immune deviation, and pruritus. While biologics and oral Janus kinase (JAK) inhibitors demonstrate high therapeutic efficacy by targeting cytokines that exert their effects via the JAK, specifically IL-4, IL-13, and IL-31, comprehensive disease control requires additional approaches that modulate JAK-independent pathways. Factors such as TNF-α, IL-25, IL-33, microbial antigens, and physical stimuli activate mitogen-activated protein kinase and nuclear factor-κB signaling in a JAK-independent manner, sustaining the disease activity. Consequently, in some cases, a strategy incorporating topical treatment that inhibits JAK-independent pathways is indispensable alongside systemic treatment. One potential strategy of this kind involves the aryl hydrocarbon receptor (AhR), ligand-activated transcription factor. Under Th2-polarized conditions, the expression of indoleamine 2,3-dioxygenase 1 (IDO1) is downregulated, limiting the availability of tryptophan-derived metabolites. This scarcity of endogenous AhR ligands subsequently compromises physiological AhR signaling. Tapinarof, a therapeutic AhR-modulating agent (TAMA), activates AhR without generating excessive reactive oxygen species. This exerts multiple effects: enhancing antioxidant defenses via nuclear factor erythroid 2-related factor 2 (NRF2) activation, restoring barrier dysfunction, suppressing Th2 inflammation, and correcting abnormalities associated with pruritus-related molecules. Furthermore, clinical trials of tapinarof have demonstrated improvement of the disease activity and pruritus, with efficacy intensifying over long-term treatment. Although adverse events such as folliculitis, acne, contact dermatitis, and headache occur, they are generally manageable by adjusting the frequency of application based on their reversibility and time of onset. Moreover, considering potential antagonism by IL-24 induced by tapinarof, combining tapinarof with systemic agents, topical therapies, or phototherapy may serve to optimize the therapeutic effects. In conclusion, AhR functions as a molecular hub integrating AD pathology, and the TAMA tapinarof expands therapeutic strategies in the treatment of AD.