Designing time-limited aryl hydrocarbon receptor drugs: A kinetic framework from the FICZ-CYP1A1 feedback axis.

The aryl hydrocarbon receptor (AHR) has been historically excluded from drug development owing to the toxicity of canonical xenobiotic agonists. Drawing on the mechanistic logic of the 6-formylindolo[3,2-b]carbazole (FICZ)-cytochrome P450 1A1 (CYP1A1) axis, we propose a spatio-kinetic design framework built on three principles: optimizing ligand residence time over binding affinity, restricting activation to target tissues through pro-drug strategies, and preserving metabolic feedback to ensure self-terminating signaling. This framework offers a concrete path to AHR modulators that recapitulate the pulse-like physiology of endogenous pathways and thereby unlock the receptor's clinical potential in autoimmunity, cancer, and barrier disorders, while avoiding the chronic activation that has historically defined its toxicity.