The Janus-facedness of the aryl hydrocarbon receptor pathway Report of the 6th International AHR Meeting: Research, Prevention, Therapy.

The ability to sense and process environmental cues is a fundamental aspect of an organism's biology. The evolutionary ancient transcription factor AHR (aryl hydrocarbon receptor) has evolved in animals to sense low molecular weight compounds derived from environmental exposure, dietary plants, the gut/skin microbiome, or generated endogenously from tryptophan upon ultraviolet light (UV) exposure or enzymatic catabolism. The binding of such molecules results in a cascade of events leading to the transcription of target genes. The AHR gene locus was first identified in mice in 1982. Since then, the beneficial and detrimental effects of AHR agonist-driven activation or lack thereof have been studied, particularly in relation to environmental chemical toxicity, carcinogenicity, or tissue homeostasis, e.g. barrier tissues. AHR ligands are also being considered as a potential new therapeutic class of molecules for the treatment of cancer, debilitating and chronic inflammatory diseases or metabolic disorders. A series of international meetings initiated twenty years ago have provided a comprehensive overview of AHR research. At the meeting in Düsseldorf in 2024, the identification of tailor-made ligands using modern, artificial intelligence (AI)-based approaches was a key topic of discussion, as were current attempts to resolve the dual nature of AHR activation - beneficial and harmful. While our understanding is still in its infancy, research was also presented that highlights previously unrecognized roles of the AHR in many diseases.