AHR

Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) family. It acts as a sensor for environmental chemicals and endogenous metabolites that influence gene expression and cellular responses.

In the resting state, AHR resides in the cytoplasm bound to chaperone proteins. When a suitable ligand binds, the receptor undergoes a conformational change, translocates to the nucleus, and dimerizes with ARNT (AHR nuclear translocator). The AHR-ARNT complex binds to xenobiotic response elements (XREs) in DNA and recruits coactivators to regulate transcription of target genes, including phase I and II enzymes such as CYP1A1, CYP1A2, and NQO1, thereby modulating xenobiotic metabolism.

Ligands for AHR range from environmental pollutants like dioxins (notably TCDD) and polycyclic aromatic hydrocarbons to endogenous compounds such as 6-formylindolo[3,2-b]carbazole (FICZ) and kynurenine. AHR activity is influenced by ligand affinity, receptor isoforms, and cellular context.

AHR influences development and immune function, affecting hematopoietic, vascular, and epithelial tissues. In mucosal and barrier tissues, it helps regulate cytokine production, antimicrobial responses, and tissue integrity, with cross-talk to other signaling pathways such as NF-kB and Wnt.

Dysregulated AHR signaling is linked to toxic responses to pollutants, certain cancers, and inflammatory or autoimmune conditions. Given its central role in xenobiotic sensing and immunity, AHR is an active target of research, with efforts to develop agonists or antagonists for disease modulation.