Vitamin B2 Sensing by the Nuclear Receptor AhR Reprograms Hepatic Metabolism [ATAC-Seq]

Nuclear receptors such as RAR/RXR and VDR directly sense vitamins A and D, but analogous sensing mechanisms for most other vitamins remain unknown. Here we identify a metabolite sensing pathway linking vitamin B2 (riboflavin) availability to an adaptive gene expression program. Riboflavin deficiency limits the FAD-dependent enzyme kynurenine 3-monooxygenase, leading to accumulation of kynurenine, an endogenous ligand of the aryl hydrocarbon receptor (AhR). Kynurenine-induced AhR nuclear translocation selectively activates poised hepatic enhancers in cooperation with AP-1 and C/EBPα, inducing glucuronidation genes and the FAD synthase gene FLAD1. This response is required to maintain intracellular FAD levels and support cell fitness under riboflavin-limiting conditions. In vivo, dietary riboflavin deficiency enhances hepatic drug clearance and reduces irinotecan toxicity. Together, these findings reveal a vitamin-sensing mechanism in which a cofactor-dependent enzyme acts as the sensor and AhR functions as the transcriptional effector that enables both flavin homeostasis and hepatic clearance capacity.