The aryl hydrocarbon receptor (AhR) as an environmental stress sensor and regulator of skin barrier function: Molecular mechanisms and therapeutic opportunities

Abstract

The aryl hydrocarbon receptor (AhR) is a transcription factor responsive to both xenobiotic and endogenous ligands involved in skin barrier adaptations in response to environmental and endogenous stressors. Due to the fundamental role that AhR-controlled signaling plays in skin barrier formation, homeostasis, resilience to environmental stressors, and damage repair, AhR-directed pharmacological strategies that aim at AhR-orchestrated signaling for anti-inflammatory, immune-modulatory, cancer chemopreventive, and barrier enhancing intervention show great therapeutic promise, delivering unique patient-directed benefit by targeting specific skin pathologies (including psoriasis, atopic dermatitis, seborrheic dermatitis, and solar radiation-induced skin photodamage) that have remained elusive and difficult to treat. The ever expanding and accessible range of chemically diverse physiological and synthetic AhR-modulators that differ with regard to pharmacokinetic and pharmacodynamic profile, AhR-directed potency, metabolic stability, and off-target effects through engagement of other signaling pathways provides a versatile and accessible compound platform of prototype agents and therapeutic leads for experimental intervention through AhR engagement, potentially representing breakthrough therapeutics that can quickly be optimized, developed, and formulated into novel AhR-directed cutaneous therapeutic entities.