| Aspect | Compact summary |
|---|---|
| Identity / verification | **Human AHR / aryl hydrocarbon receptor**, UniProt **P35869**; ligand-activated **bHLH-PAS** transcription factor. Domain organization reported as **bHLH** (DNA binding/dimerization), **PAS-A** (heterodimer stability), **PAS-B** (principal ligand-binding pocket), and **C-terminal transactivation domain**; one review gives boundaries **bHLH aa 33–87, PAS-A aa 111–273, PAS-B aa 275–386, TAD aa 490–805**. This matches the requested human AHR protein/domain context (pqac-00000003, pqac-00000006, pqac-00000007, pqac-00000008). |
| Resting state / localization | Inactive AHR is mainly **cytosolic** in a multiprotein complex with **HSP90 (dimer), AIP/XAP2, p23, and c-SRC/SRC**; HSP90 helps maintain ligand-responsive conformation and masks/exposes trafficking/DNA-binding functions until activation (pqac-00000001, pqac-00000002, pqac-00000006, pqac-00000007, pqac-00000015). |
| Canonical activation steps | **Ligand binds PAS-B → conformational change → AIP dissociation / NLS exposure → nuclear import (importin-β / transportin pathways reported) → heterodimerization with ARNT (HIF-1β) → binding to XRE/DRE motifs** (consensus reported as **5'-TNGCGTG-3'**, also core **GCGTG/TTGCGTG**) → transcription of the “AHR gene battery”; negative feedback via **AHRR**, **TIPARP/TiPARP**, **CYP1-mediated ligand metabolism**, and proteasomal degradation (pqac-00000001, pqac-00000004, pqac-00000005, pqac-00000006, pqac-00000007, pqac-00000015). |
| Structural advance | 2025 structural work solved **AHR-ARNT-DNA complexes with 6 ligands** (**tapinarof, FICZ, benzo[a]pyrene, β-naphthoflavone, indigo, indirubin**) and described a ligand-driven transition from chaperone engagement to ARNT-stabilized active complex; porcine and human N-terminal halves showed **91% sequence identity** and **66/71 interacting residues identical** (pqac-00000002). |
| Key exogenous ligands | Classic xenobiotic/toxic ligands include **TCDD**, **benzo[a]pyrene (BaP)**, **β-naphthoflavone (BNF)**; therapeutic/experimental agonists include **tapinarof** and **indirubin/indigo**. High-affinity ligands such as **TCDD** can produce prolonged signaling (pqac-00000002, pqac-00000005, pqac-00000007). |
| Key endogenous / physiological ligands | Endogenous and host-/microbiome-derived agonists include **FICZ** (UV/tryptophan photoproduct), **kynurenine (Kyn)**, **kynurenic acid (KYNA)**, **bilirubin**, dietary indole precursors such as **indole-3-carbinol (I3C)** and metabolites such as **DIM/ICZ/TEACOPs**, plus microbial indole pathways linking AHR to barrier and immune homeostasis (pqac-00000001, pqac-00000005, pqac-00000006). |
| Primary canonical target genes | Strongly recurrent transcriptional targets: **CYP1A1, CYP1A2, CYP1B1** (canonical biomarkers of activation), plus **AHRR** and **TIPARP/TiPARP**; additional reported targets include **NQO1**, **TDO2**, **IDO1**, **IL10, IL17, IL22**, **CD39, CD73**, and some **ABC transporters**, depending on cell context (pqac-00000001, pqac-00000005, pqac-00000006, pqac-00000007). |
| Core biological function | Best-supported primary function is as a **small-molecule sensor and transcriptional regulator** coupling exposure to environmental, dietary, microbial, and endogenous metabolites to **xenobiotic metabolism**, especially induction of phase I enzymes that metabolize ligands and other substrates; this also creates feedback and, in some cases, bioactivation of procarcinogens (e.g., **BaP → BPDE**) (pqac-00000001, pqac-00000003, pqac-00000007). |
| Barrier / immune roles | AHR has well-supported roles in **skin and gut barrier maintenance** and **immune regulation**, especially through tryptophan/microbiome ligands and cytokine programs such as **IL-22** and **IL-10**; reviews emphasize strong activity in barrier tissues (**skin, gut, lung**) and immune cells including Th17/ILC3-associated programs (pqac-00000001, pqac-00000002, pqac-00000003, pqac-00000006). |
| Non-canonical signaling: transcriptional cross-talk | AHR also signals beyond XRE-driven transcription via interactions with **NF-κB (RelA/RelB)**, **c-MAF**, **KLF6**, and other TFs; one review highlights **SOCS2 induction** suppressing TLR/NF-κB-dependent cytokines (**IL-6, IL-12A/B, IL-23A, TNF**) (pqac-00000005, pqac-00000007). |
| Non-canonical signaling: E3 ligase / adaptor roles | Activated AHR can assemble a **CUL4B-based E3 ubiquitin ligase (CUL4B^AHR)** that promotes degradation of **ER-α, AR, β-catenin, PPARγ**; cytoplasmic ligand-AHR can also act as an **adaptor/scaffold** linking **SRC/JAK2** to **PI3K-AKT**, **MEK-ERK**, and **YAP-ERK** signaling. A dose-dependent switch between transcriptional and E3-ligase functions has been reported for some ligands (e.g., indoxyl sulfate) (pqac-00000004). |
| Real-world application: approved dermatology drug | **Tapinarof 1% cream** is a topical **AHR agonist/modulator**. Two phase 3 psoriasis trials (**PSOARING 1 and 2**) enrolled **683 adults**; by **week 12**, **up to 40%** achieved **PGA 0/1** versus up to 6% vehicle, and **up to 47%** achieved **PASI-75** versus up to 10% vehicle. **FDA approval: May 2022** for adult plaque psoriasis; described as the first-in-class AHR-modulating drug. Long-term extension (**PSOARING 3**) reported maintained response for **at least 4 months** off treatment (pqac-00000011, pqac-00000010, pqac-00000001). |
| Additional dermatology implementation | **Benvitimod** (tapinarof-related AHR modulator) is noted as **approved in China** after phase 3 testing, with different formulation/dosing from tapinarof (pqac-00000011). |
| Ongoing / new indication trial for tapinarof | **NCT06661213**: topical tapinarof for **cutaneous lupus erythematosus**; **Early Phase 1**, open-label, enrolling by invitation; **estimated enrollment 10**, started **2025-04-03**; evaluates Week-16 CLA/CLASI activity outcomes (pqac-00000014). |
| Oncology antagonist program | **IK-175** is an oral **AHR antagonist/inhibitor** in oncology development. **NCT04200963** (phase 1a/b, single agent and with nivolumab in advanced/metastatic solid tumors and urothelial carcinoma) is listed as **completed** with **enrollment 78** in trial-search results; broader review literature cites IK-175 as part of early-stage oncology programs (pqac-00000009). |
| Withdrawn IK-175 study | **NCT05472506**: IK-175 + **nivolumab** for primary PD-1-resistant metastatic/recurrent **HNSCC**; **Phase 1b**, randomized dose-expansion, but **withdrawn by sponsor decision** with **actual enrollment 0** and no results reported (pqac-00000013). |
| Broader development landscape | A 2025 drug-discovery review notes **BAY2416964** and **IK-175** in oncology and states **~20 additional trials** of AHR modulation (endogenous, dietary, synthetic ligands), underscoring active translational exploitation of AHR as a therapeutic node (pqac-00000009). |


*Table: This table condenses verified functional annotation for human AHR (UniProt P35869), covering domain architecture, canonical and non-canonical signaling, major ligand classes, target genes, and current translational applications. It also captures key quantitative clinical figures for tapinarof and IK-175 that are useful for rapid reference.*