Ligand- and tissue-specific differences in the activation of the aryl hydrocarbon receptor by flavonoids: A focus on baicalein and scutellarein.

Flavonoids are natural dietary modulators of the aryl hydrocarbon receptor (AHR) with considerable therapeutic potential. However, their safety and efficacy remain difficult to predict due to the complex, ligand- and tissue-specific differences of AHR. In this study, we combined transcriptional and protein-level experiments with computational methods, including molecular docking and R-based RNA-seq analyses, to elucidate the patterns of cell type-specific activation of AHR by structurally similar flavonoids. Among six tested flavonoids, baicalein (Ba) and scutellarein (Sc) were the most potent AHR activators based on a bio-detection system and were further confirmed as potential AHR ligands through molecular docking. Mechanistic studies revealed that Ba significantly increased CYP1A1 expression in HepG2 cells and CYP1B1 expression in U87 cells through the AHR pathway. Interestingly, Sc induced AHR-dependent CYP1B1 expression in U87 cells but exerted partial AHR-dependent effects on CYP1A1 expression in HepG2 cells. These findings highlight cell type-specific regulatory patterns that may reflect tissue-specific regulation of the AHR pathway induced by structurally similar flavonoids, contributing to providing further mechanistic insights into their toxicological and pharmacological properties. Overall, this work offers a scientific basis for the development and safety assessment of flavonoid-based nutraceuticals and therapeutic agents.