The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor regulating the expression of genes, for instance encoding the monooxygenases cytochrome P450 (CYP) 1A1 and CYP1A2, which are important enzymes in metabolism of xenobiotics. The AHR is activated upon binding of polycyclic aromatic hydrocarbons (PAHs), persistent organic pollutants (POPs), and related ubiquitous environmental chemicals, to mediate their biological and toxic effects. In addition, several endogenous and natural compounds can bind to AHR, thereby modulating a variety of physiological processes. In recent years, ambient particulate matter (PM) associated with traffic related air pollution (TRAP) has been found to contain significant amounts of PAHs. PM containing PAHs are of increasing concern as a class of agonists, which can activate the AHR. Several reports show that PM and AHR-mediated induction of CYP1A1 results in excessive generation of reactive oxygen species (ROS), causing oxidative stress. Furthermore, exposure to PM and PAHs induce inflammatory responses and may lead to chronic inflammatory diseases, including asthma, cardiovascular diseases, and increased cancer risk. In this review, we summarize findings showing the critical role that the AHR plays in mediating effects of environmental pollutants and stressors, which pose a risk of impacting the environment and human health.

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor of the bHLH/PAS protein family. In this review, we explore the multifaceted roles of AHR in both health and disease, tracing its recognition as a xenobiotic sensor and a central regulator of physiological homeostasis. We begin by recounting six decades of discoveries that have shaped our understanding of AHR, from its canonical function in environmental sensing to its critical roles in development, immune regulation, barrier tissue integrity, and host–microbe interactions. We detail recent structural breakthroughs that have illuminated the ligand-binding mechanisms and regulation of AHR, providing key insights into its activation and transcriptional control. We also highlight the diversity of AHR ligands, ranging from environmental toxins to microbial and dietary metabolites of tryptophan, and their context-dependent effects on AHR activation through the canonical pathway and noncanonical signaling mechanisms. We examine the involvement of AHR in pathologies such as cancer and autoimmune and inflammatory diseases and its potential as a therapeutic target. Finally, emphasis is placed on recent advances and future developments in drug design, aiming to develop modulators with clinical efficacy. This comprehensive synthesis underscores the dual role of AHR as a master integrator of both environmental and endogenous cues. Placing AHR within broader frameworks, such as the exposome, opens new avenues for therapeutic innovation and more effective strategies for disease prevention.

The skin is constantly exposed to a variety of environmental threats, including solar electromagnetic radiation, microbes, airborne particulate matter, and chemicals. Acute exposure to these environmental factors results in the activation of different signaling pathways that orchestrate adaptive stress responses to maintain cell and tissue homeostasis. Chronic exposure of skin to these factors, however, may lead to the accumulation of damaged macromolecules and loss of cell and tissue integrity, which, over time, may facilitate aging processes and the development of aging-related malignancies. One transcription factor that is expressed in all cutaneous cells and activated by various environmental stressors, including dioxins, polycyclic aromatic hydrocarbons, and ultraviolet radiation, is the aryl hydrocarbon receptor (AHR). By regulating keratinocyte proliferation and differentiation, epidermal barrier function, melanogenesis, and immunity, a certain degree of AHR activity is critical to maintain skin integrity and to adapt to acute stress situations. In contrast, a chronic activation of cutaneous AHR signaling critically contributes to premature aging and the development of neoplasms by affecting metabolism, extracellular matrix remodeling, inflammation, pigmentation, DNA repair, and apoptosis. This article provides an overview of the detrimental effects associated with sustained AHR activity in chronically stressed skin and pinpoints AHR as a promising target for chemoprevention.

Ultraviolet B (UVB) radiation induces mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPDs), in epidermal keratinocytes (KC). To prevent skin carcinogenesis, these DNA photoproducts must be removed by nucleotide excision repair (NER) or apoptosis. Here we report that the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of UVB-induced CPDs in human HaCaT KC and skin from SKH-1 hairless mice. Subsequent RNA interference and inhibitor studies in KC revealed that AHR specifically suppresses global genome but not transcription-coupled NER. In further experiments, we found that the accelerated repair of CPDs in AHR-compromised KC depended on a modulation of the p27 tumor suppressor protein. Accordingly, p27 protein levels were increased in AHR-silenced KC and skin biopsies from AHR^−/− mice, and critical for the improvement of NER. Besides increasing NER activity, AHR inhibition was accompanied by an enhanced occurrence of DNA double-strand breaks triggering KC apoptosis at later time points after irradiation. The UVB-activated AHR thus acts as a negative regulator of both early defense systems against carcinogenesis, NER and apoptosis, implying that it exhibits tumorigenic functions in UVB-exposed skin. In fact, AHR^−/− mice developed 50% less UVB-induced cutaneous squamous cell carcinomas in a chronic photocarcinogenesis study than their AHR^+/+ littermates. Taken together, our data reveal that AHR influences DNA damage-dependent responses in UVB-irradiated KC and critically contributes to skin photocarcinogenesis in mice.