The landscape of biased agonism in aryl hydrocarbon receptor signaling: current clues and future directions

Our understanding of the aryl hydrocarbon receptor (AhR) signaling pathway has significantly advanced since its initial discovery, revealing roles in both toxicology and normal physiological processes like immunity and organ development. However, key gaps remain concerning the precise mechanisms governing ligand-dependent canonical and non-canonical signaling. From a pharmacological standpoint, this involves the concept of functional selectivity, also known as biased agonism, where different ligands can selectively activate distinct downstream pathways, leading to different biological or toxicological outcomes. This paper reviews the current understanding of the formation, composition, and function of both cytosolic and nuclear AhR multiprotein complexes. We analyze the early and late cellular events that follow AhR ligand binding and explore new approaches aimed at the selective targeting of the AhR canonical and non-canonical signaling pathways for potential therapeutic benefit.