Aryl hydrocarbon receptor–Nuclear factor erythroid 2-related factor 2 pathway (AHR–Nrf2 pathway) (AHR–Nrf2 pathway)

The Aryl hydrocarbon receptor (AHR)–Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is a critical signaling axis that maintains intestinal homeostasis and epithelial barrier integrity (Yu et al., 2021, Front Immunol). AHR is a ligand-activated transcription factor that senses environmental, dietary, and microbial signals, such as indole derivatives from the gut microbiota. Upon activation, AHR directly induces the transcription of Nrf2 by binding to xenobiotic response elements (XREs) in the Nrf2 promoter, creating a robust cytoprotective response (Miao et al., 2005, J Biol Chem). In intestinal epithelial cells, this pathway regulates the expression of tight junction proteins like Occludin and Zonula Occludens-1 (ZO-1), which are essential for preventing the translocation of pathogens and toxins (Lamas et al., 2016, Nature). Furthermore, the pathway promotes the production of interleukin-22 (IL-22), a cytokine vital for mucosal healing and antimicrobial peptide production. Dysregulation of the AHR–Nrf2 axis is implicated in inflammatory bowel disease (IBD) and colorectal cancer, making it a significant therapeutic target for restoring gut barrier function (Rothhammer & Quintana, 2019, Nat Rev Immunol). Pharmacological agents targeting this pathway include AHR agonists like Tapinarof and Nrf2 activators like Dimethyl fumarate, which aim to mitigate oxidative stress and chronic inflammation (Smith et al., 2022, J Clin Invest).

Other names

AHR-NFE2L2 axisAHR-Nrf2 signaling axisAryl hydrocarbon receptor-Nrf2 crosstalkAHR-Nrf2 pathway

The AHR–Nrf2 pathway operates through a crosstalk mechanism where ligand-activated AHR binds to xenobiotic response elements (XREs) in the Nrf2 (NFE2L2) promoter, inducing its transcription. This leads to the coordinated upregulation of antioxidant enzymes (e.g., HO-1, NQO1) and the reinforcement of intestinal barrier proteins (e.g., ZO-1, Occludin), while also modulating immune responses via IL-22 production.