AHRIs

Aryl hydrocarbon receptor inhibitors (AHRIs) are chemical compounds designed to dampen the signaling of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor involved in xenobiotic metabolism, immune regulation, and development. AHRIs can act by competing with endogenous or exogenous ligands for AHR binding, by blocking receptor dimerization with ARNT, or by preventing receptor translocation to the nucleus, thereby reducing transcription of AHR target genes such as CYP1A1.

AHR is activated by a range of planar aromatic compounds, including environmental pollutants like dioxins and polycyclic aromatic hydrocarbons, as well as some endogenous metabolites. In normal physiology, AHR participates in detoxification pathways and immune homeostasis. However, chronic AHR activation has been linked to toxicity and disease risk, while in other contexts AHR signaling can contribute to protective responses. Because of these diverse roles, AHR inhibition is explored as a means to modulate excessive or pathogenic AHR activity without completely suppressing normal receptor function.

AHRIs are being investigated as potential therapeutics in inflammatory diseases, autoimmune conditions, fibrosis, and certain cancers where aberrant AHR signaling is implicated. The goal is to reduce harmful signaling while preserving beneficial AHR functions. This balance requires selective, tissue-targeted approaches and careful consideration of context-dependent effects.

Examples of AHRIs include CH-223191, a widely used research tool that inhibits AHR by blocking ligand-induced nuclear translocation, and other synthetic inhibitors such as GNF351. Some natural products have also been described as AHR antagonists, though their potency and specificity vary. Overall, research on AHRIs remains primarily in preclinical stages, with ongoing exploration of safety, selectivity, and clinical potential.