The Expanding Landscape of Aryl Hydrocarbon Receptor Ligands and Signaling Pathways: Implications for Immune Regulation and Disease

Articles in Press

Document Type : Review article

Authors

1 The Islamic University, Najaf, Iraq

2 Pharmacognosy and Phytochemistry Department, College of Pharmacy, The Islamic University, Najaf, Iraq.

3 Al-Zahrawi University college

4 Department of Medical Laboratory Techniques, College of Health and Medical Techniques, University of Alkafeel. Najaf, Iraq

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand‑activated transcription factor first identified as a sensor of halogenated and polycyclic aromatic hydrocarbons but now recognised as a wide‑ranging regulator of development, metabolism and immunity. In its resting state it forms a cytosolic chaperone complex; ligand binding prompts nuclear translocation, dimerisation with the AHR nuclear translocator and induction of detoxifying genes, while non‑genomic signalling via tyrosine kinases and ubiquitin ligase activity further broadens its influence. Yet AHR is not solely a xenobiotic receptor: its ligand landscape now spans endogenous tryptophan metabolites, lipid mediators, bile pigments, and a host of dietary and microbiota‑derived compounds such as polyphenols, glucosinolates and terpenoids. A growing body of evidence demonstrates that variations in ligand origin, binding affinity, and metabolic stability directly determine the direction and magnitude of AHR-mediated signalling. For example, the high-affinity xenobiotic TCDD produces sustained AHR activation leading to toxic dysregulation of CYP1A1, whereas the endogenous metabolite FICZ induces only transient activation due to rapid degradation by CYP1A1. Similarly, microbiota-derived indole derivatives have been shown to enhance mucosal tolerance by increasing IL-22 production. These findings highlight that AHR integrates signals across TGF-β/BMP, Notch, Wnt/β-catenin and NF-κB pathways in a context-dependent manner, and that dietary and microbial sources of ligands play a measurable role in shaping immune and metabolic outcomes. Establishing these mechanistic relationships will help guide the development of selective AHR modulators that maximize therapeutic benefit while minimizing the toxicities associated with classical ligands. This diversity raises compelling questions: how do differences in ligand origin, affinity and half‑life shape the receptor’s downstream signalling? Why do certain ligands drive inflammatory programmes while others promote tolerance? Can this biochemical specificity be harnessed to develop safe therapeutics? These questions gain urgency given that AHR intersects with TGF‑β/BMP, Notch, Wnt/β‑catenin and NF‑κB pathways, making outcomes highly context‑dependent. Clarifying these interactions and exploring how diet and the microbiome modulate AHR will open new avenues for exploiting this receptor while avoiding the well‑known toxicities associated with classical ligands.

Keywords

Iranian Journal of Veterinary Medicine

Articles in Press, Accepted Manuscript
Available Online from 19 May 2026

Files

Share

How to cite

Statistics