Aryl hydrocarbon receptor regulates programmed cell death in diseases: molecular mechanisms and therapeutic implications.

The aryl hydrocarbon receptor (AHR), which is a ligand-activated transcription factor, controls complex transcription programs in a ligand-specific, cell type-specific, and context-specific manner by integrating signals from the environment, diet, microorganisms, and metabolism. Emerging evidence indicates that AHR participates in the regulation of multiple cell death pathways, including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, playing a crucial role in influencing the pathogenesis of diseases. Originally identified as a sensor for environmental toxins, AHR is now recognized for its interactions with both endogenous and microbial ligands, allowing it to orchestrate complex biological processes. This review synthesizes current knowledge on the structural dynamics, ligand diversity, and activation mechanisms of AHR, while highlighting its dual roles in programmed cell death (PCD). Additionally, we discuss the significance of AHR-regulated cell death in inflammatory diseases, neurological disorders, respiratory diseases, and cancer, highlighting its potential as a therapeutic target for various human conditions.