The Therapeutic Effect of Tapinarof on In Vitro Cutaneous Lupus-like Keratinocyte Model.

Cutaneous lupus erythematosus (CLE) is an autoimmune disease in which type I interferon (IFN) has been well-established as a central pathogenic factor. It presents with diverse cutaneous manifestations that markedly impair patients' quality of life. Therapeutic options for CLE remain limited and are often insufficient, highlighting the need for novel treatment strategies. The aryl hydrocarbon receptor (AHR) is a transcription factor that modulates immune responses and has recently attracted attention as a potential therapeutic target for autoimmune diseases. We previously confirmed that treatment of normal human epidermal keratinocytes with IFNα and Poly I:C upregulated the expression of the CLE-like inflammatory cytokines IFNκ, CXCL10, and IL6, as well as the B-cell activating factor. In the present study, we demonstrated by quantitative PCR and Western blotting that pretreatment with the AHR agonist tapinarof suppressed the upregulation of IFNκ and CXCL10. Mechanistically, we demonstrated that tapinarof suppresses IFNκ expression by inhibiting STAT1 phosphorylation in an AHR-dependent manner, thereby attenuating the nuclear translocation of ISGF3. Overall, we show that tapinarof suppresses CLE-like inflammation in human keratinocytes in an AHR-dependent manner, suggesting that it may represent a novel therapeutic agent for CLE.