{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Recent studies have elucidated a multifaceted role for the aryl hydrocarbon receptor repressor (AHRR) in modulating cellular responses to environmental toxicants and regulating cell growth, differentiation, and immune function. AHRR functions as a negative feedback regulator within the aryl hydrocarbon receptor (AHR) signaling cascade by directly binding to xenobiotic response elements and recruiting corepressor complexes—a process further refined by posttranslational modifications such as SUMOylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " This repression of AHR‐mediated transcription serves to temper the response to ligands including dioxins and polycyclic aromatic hydrocarbons."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Epigenetic modifications of AHRR, notably hypomethylation at key CpG sites (e.g., cg05575921), are highly sensitive to environmental exposures such as tobacco smoke and PAHs. Such methylation changes have been robustly linked to exposure in both adult and prenatal contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": " These epigenetic marks not only serve as biomarkers that sensitively reflect even low levels of exposure but may also contribute to downstream pathophysiological processes such as atherogenesis."}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its role in environmental sensing, functional studies indicate that loss or downregulation of AHRR contributes to tumorigenesis. Downregulation via DNA hypermethylation or gene fusions, which disrupt its repressor domain, has been demonstrated in multiple cancers and is associated with increased cellular proliferation, migration, invasion, and angiogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " In parallel, studies in immune cells reveal that AHRR exerts cell type–specific effects on inflammatory responses, contributing to the fine balance between immune activation and suppression in contexts such as systemic endotoxin shock and intestinal inflammation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Genetic variation in AHRR, particularly the Pro185Ala polymorphism, further modulates its repressive capacity and has been associated with susceptibility to reproductive disorders such as male infertility and endometriosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Collectively, these findings underscore the central role of AHRR as an environmental sensor and regulator of AHR signaling, linking epigenetic and genetic variation to diverse pathophysiological outcomes ranging from cancer progression to immune dysregulation.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Motohiko Oshima, Junsei Mimura, Hiroki Sekine, et al. 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