The aryl hydrocarbon receptor(AHR)is a ligand-dependent transcription factor of the bHLH/PAS protein family.In this review,we explore the multifaceted roles of AHR in both health and disease,tracing its recognition as...The aryl hydrocarbon receptor(AHR)is a ligand-dependent transcription factor of the bHLH/PAS protein family.In this review,we explore the multifaceted roles of AHR in both health and disease,tracing its recognition as a xenobiotic sensor and a central regulator of physiological homeostasis.We begin by recounting six decades of discoveries that have shaped our understanding of AHR,from its canonical function in environmental sensing to its critical roles in development,immune regulation,barrier tissue integrity,and host-microbe interactions.We detail recent structural breakthroughs that have illuminated the ligand-binding mechanisms and regulation of AHR,providing key insights into its activation and transcriptional control.We also highlight the diversity of AHR ligands,ranging from environmental toxins to microbial and dietary metabolites of tryptophan,and their contextdependent effects on AHR activation through the canonical pathway and noncanonical signaling mechanisms.We examine the involvement of AHR in pathologies such as cancer and autoimmune and inflammatory diseases and its potential as a therapeutic target.Finally,emphasis is placed on recent advances and future developments in drug design,aiming to develop modulators with clinical efficacy.This comprehensive synthesis underscores the dual role of AHR as a master integrator of both environmental and endogenous cues.Placing AHR within broader frameworks,such as the exposome,opens new avenues for therapeutic innovation and more effective strategies for disease prevention.展开更多
基金supported by Inserm,CNRS,the University of Montpellier,the French National Research Agency(ANR),grant No.ANR-23-CE34-0006-01(SYNERGY)the French Agency for Food,Environmental and Occupational Health&Safety(ANSES),grant No.EST-24-013(AHRtox)+7 种基金kindly supported by the Fraunhofer Cluster of Excellence Immune-Mediated Diseases(grant CIMD_CED-AhR)the German Federal Ministry of Education and Research(grant CED-AhR)the National Institutes of Health Grant ES028244(GHP).B.P.L.is currently supported,in part,by grants P30ES001247,R01ES030300 and R01ES036197 from the US National Institute of Environmental Health Science,National Institutes of Health.P.M.-Athe European Union’s Horizon 2020 research and innovation program under grant agreement number 951921NORTE2030-FEDER-01777300-SCALE-ImmunoHUB2030 supported by Norte Portugal Regional Operational Programme(NORTE 2030),under the PORTUGAL 2030 Partnership Agreement,through the European Regional Development Fund(FEDER),and COMPETE2030-FEDER-00693400supported by FEDER and national Funds(Fundação para a Ciência e Tecnologia,FCT),operation number 15824 relative to applications to MPr-2023-12support from the German Research Foundation(SFB1389 UNITE-Glioblastoma,project No.404521405)and the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(grant agreement number 101045257,CancAHR)supported by the Deutsche Forschungsgemeinschaft,grants ES 103/11-1,HA 7346/5-1 and HA 7346/6-1.
文摘The aryl hydrocarbon receptor(AHR)is a ligand-dependent transcription factor of the bHLH/PAS protein family.In this review,we explore the multifaceted roles of AHR in both health and disease,tracing its recognition as a xenobiotic sensor and a central regulator of physiological homeostasis.We begin by recounting six decades of discoveries that have shaped our understanding of AHR,from its canonical function in environmental sensing to its critical roles in development,immune regulation,barrier tissue integrity,and host-microbe interactions.We detail recent structural breakthroughs that have illuminated the ligand-binding mechanisms and regulation of AHR,providing key insights into its activation and transcriptional control.We also highlight the diversity of AHR ligands,ranging from environmental toxins to microbial and dietary metabolites of tryptophan,and their contextdependent effects on AHR activation through the canonical pathway and noncanonical signaling mechanisms.We examine the involvement of AHR in pathologies such as cancer and autoimmune and inflammatory diseases and its potential as a therapeutic target.Finally,emphasis is placed on recent advances and future developments in drug design,aiming to develop modulators with clinical efficacy.This comprehensive synthesis underscores the dual role of AHR as a master integrator of both environmental and endogenous cues.Placing AHR within broader frameworks,such as the exposome,opens new avenues for therapeutic innovation and more effective strategies for disease prevention.
