Aryl hydrocarbon receptor pharmacology-mechanisms, ligands, and therapeutic potential

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that has emerged as a key modulator of several physiological and pathological processes. Historically, AHR has been studied for its role as a mediator of the toxic responses of environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Because of this, its potential as a therapeutic target was overlooked. AHR is now regarded as a multifunctional regulator of inflammation, immunity, barrier tissue integrity, metabolism, and cancer biology. AHR signaling is modulated by an array of structurally diverse endogenous, microbial, dietary, pharmaceutical, and xenobiotic ligands. AHR exhibits extensive crosstalk with many signaling pathways, which contributes to highly context-specific biological outcomes. Recent advances and enhanced interest in AHR pharmacology have accelerated the development of therapeutically relevant AHR ligands, including the clinically approved AHR agonist, tapinarof, for the treatment of psoriasis and atopic dermatitis, as well as emerging AHR antagonist strategies in cancer immunotherapy. Structural efforts have succeeded in providing valuable insight into ligand-AHR interactions that will further contribute to improved and rational design of AHR ligands. However, significant challenges remain, including AHR ligand promiscuity, complex negative feedback regulation, extensive signaling crosstalk, and long-term safety concerns. Here, we review the molecular mechanisms of AHR activation, its physiological and pathological functions, and the current advances of its therapeutic targeting. SIGNIFICANCE STATEMENT: The aryl hydrocarbon receptor (AHR) has emerged from its origins in toxicology to become a promising clinically relevant target for the treatment of dermatological, gastroenterological, and autoimmune diseases as well as cancer. This review summarizes the current knowledge of AHR pharmacology, including molecular signaling, endogenous and exogenous ligands, physiological and pathological functions, present and emerging therapeutic targeting strategies, as well as challenges that remain for translation into safe clinical therapies.