Affinage

NR1I3

Nuclear receptor subfamily 1 group I member 3 · UniProt Q14994

Round 2 corrected
Length
352 aa
Mass
39.9 kDa
Annotated
2026-04-29
130 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NR1I3 (CAR) is a liver-enriched nuclear receptor that functions as a master xenobiotic sensor and transcriptional regulator of hepatic drug metabolism, bilirubin clearance, and energy homeostasis. It heterodimerizes with RXRα and binds DR-5 and ER-6 response elements on target gene promoters (CYP2B6, CYP3A4, CYP2C8, CYP2C9, UGT1A1) with constitutive transcriptional activity conferred by a unique Helix X that locks the AF-2 activation domain in an active conformation, enabling ligand-independent coactivator recruitment; endogenous androstane metabolites act as inverse agonists by promoting coactivator release (PMID:9783588, PMID:15610735). CAR resides in a cytoplasmic retention complex and translocates to the nucleus upon direct agonist binding (e.g., CITCO) or indirect signal-mediated activation, where it induces phase I/II detoxification enzymes and bilirubin-clearance genes, while suppressing PPARα-, HNF4α-, and FXR-dependent metabolic programs through competitive co-occupancy of shared enhancers (PMID:12611900, PMID:12644704, PMID:30396153). Chronic CAR activation in rodent liver promotes hepatocarcinogenesis through Mdm2 upregulation and p53 suppression, whereas inflammatory cytokines (IL-1β) suppress CAR transcription via NF-κB-mediated chromatin remodeling at its promoter (PMID:15831521, PMID:15382119).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1994 High

    The initial cloning of NR1I3 (MB67) established it as a liver-enriched orphan nuclear receptor that heterodimerizes with RXR and exhibits constitutive (ligand-independent) transactivation on DR-5 elements, posing the question of how a nuclear receptor could be active without a known ligand.

    Evidence Receptor cloning, gel shift assays, and reporter assays in transfected cells

    PMID:8114692

    Open questions at the time
    • No endogenous ligand identified
    • Mechanism of constitutive activity unknown
    • In vivo target genes undetermined
  2. 1998 High

    The mystery of constitutive activity was resolved by showing that CAR recruits coactivators without ligand, while androstanol and androstenol function as inverse agonists that release coactivators, defining a novel regulatory paradigm for nuclear receptors.

    Evidence In vitro coactivator interaction assays with stereospecific androstane structure-activity analysis

    PMID:9783588

    Open questions at the time
    • Structural basis for constitutive coactivator docking unknown
    • Physiological relevance of androstane inverse agonism in vivo unconfirmed
  3. 2000 High

    Demonstration that CAR and PXR cross-regulate each other's target CYP genes through shared response elements established the concept of an overlapping xenobiotic sensor network rather than a one-receptor-one-target model.

    Evidence Reporter assays and transgenic mouse studies across CYP2B and CYP3A promoters

    PMID:11114890

    Open questions at the time
    • Genome-wide extent of overlap not mapped
    • Mechanisms determining preferential receptor usage at shared elements unclear
  4. 2002 High

    Genetic loss-of-function studies using CAR-null mice proved that CAR is required for acetaminophen hepatotoxicity and mapped specific CAR-dependent CYP target genes essential for acetaminophen bioactivation, linking CAR activity directly to drug toxicity outcomes.

    Evidence CAR knockout mice challenged with acetaminophen; pharmacological rescue with androstanol inverse agonist

    PMID:12376703

    Open questions at the time
    • Human relevance of CAR-dependent acetaminophen toxicity not directly tested
    • Full spectrum of CAR-regulated acetaminophen-metabolizing enzymes not enumerated
  5. 2003 High

    CAR was shown to coordinate the entire bilirubin-clearance pathway (uptake, conjugation, excretion), with bilirubin itself acting as a direct CAR activator; low neonatal CAR expression was linked to neonatal jaundice susceptibility, establishing CAR's role in endobiotic homeostasis beyond xenobiotic sensing.

    Evidence CAR knockout and humanized CAR mouse models with bilirubin clearance assays and receptor activation studies

    PMID:12644704

    Open questions at the time
    • Direct structural evidence for bilirubin binding to CAR LBD absent
    • Contribution of CAR variants to clinical neonatal jaundice not tested
  6. 2003 High

    Identification of CITCO as the first selective human CAR agonist provided a critical pharmacological tool, enabling distinction of CAR- vs PXR-mediated gene regulation and confirming CYP2B6 as a prototypical CAR target gene.

    Evidence Fluorescence-based receptor activation, nuclear translocation assay, and primary human hepatocyte gene expression profiling

    PMID:12611900

    Open questions at the time
    • CITCO selectivity in vivo at physiological doses not fully established
    • Structural basis for CITCO selectivity over PXR unknown
  7. 2004 High

    The crystal structure of the CAR/RXRα heterodimer revealed a unique single-turn Helix X that restricts AF-2 conformational freedom, providing the structural explanation for constitutive coactivator recruitment and answering the long-standing question of how CAR achieves ligand-independent activity.

    Evidence X-ray crystallography of the human CAR/RXRα heterodimer complex

    PMID:15610735

    Open questions at the time
    • Structure of CAR bound to inverse agonist not resolved
    • Dynamics of Helix X upon androstanol binding not captured
  8. 2004 High

    IL-1β/NF-κB was found to suppress CAR expression via interference with GR-mediated CAR promoter transactivation and chromatin remodeling (reduced H4 acetylation), providing a molecular mechanism for inflammation-mediated downregulation of drug metabolism.

    Evidence ChIP, reporter assays, NF-κB overexpression/inhibitor studies in human hepatocytes

    PMID:15382119

    Open questions at the time
    • Contribution of additional inflammatory cytokines to CAR suppression not systematically studied
    • In vivo chromatin remodeling at the CAR locus during inflammation not confirmed
  9. 2005 High

    Chronic CAR activation was shown to cause hepatocarcinogenesis in mice through direct upregulation of Mdm2 and suppression of p53-mediated apoptosis, identifying a specific oncogenic mechanism and distinguishing acute protective xenobiotic responses from chronic tumorigenic risk.

    Evidence CAR knockout mouse carcinogenesis models with Mdm2 expression analysis and apoptosis/DNA replication assays

    PMID:15831521

    Open questions at the time
    • Human relevance disputed — evidence suggests tumor-suppressive role of CAR in human liver
    • Direct CAR binding to the Mdm2 promoter not confirmed by ChIP
  10. 2008 High

    CAR was established as a metabolic regulator beyond drug metabolism: its activation suppresses PPARα expression and fatty acid oxidation genes, increasing serum triglycerides, while CAR deletion normalizes hypertriglyceridemia in obese mice.

    Evidence Car knockout crossed with ob/ob mice, high-fat diet model, TCPOBOP activation, PPARα target gene and fatty acid oxidation assays

    PMID:18941143

    Open questions at the time
    • Whether CAR directly binds PPARα regulatory elements or acts indirectly unknown
    • Human metabolic relevance of CAR-PPARα antagonism not established
  11. 2018 High

    Genome-wide ChIP-seq in mouse liver revealed that CAR stimulates target genes with increased H4K5 acetylation but inhibits metabolic genes by co-binding enhancers occupied by HNF4α, PPARα, and FXR, establishing competitive enhancer co-occupancy as the mechanism for CAR-mediated metabolic reprogramming.

    Evidence ChIP-seq for CAR, RXRα, and H4K5Ac genome-wide in drug-activated mouse liver integrated with transcriptomics

    PMID:30396153

    Open questions at the time
    • Human liver ChIP-seq for CAR not performed
    • Coactivator/corepressor dynamics at competitively bound enhancers not resolved
    • Single-cell heterogeneity of CAR-bound enhancer states not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of inverse agonist-induced conformational change, the identity and regulation of the cytoplasmic CAR retention complex components, species-specific differences in CAR's role in liver tumorigenesis versus tumor suppression, and the genome-wide CAR cistrome in human liver.
  • No inverse agonist-bound CAR crystal structure
  • Cytoplasmic retention complex composition incompletely defined
  • Human hepatic CAR ChIP-seq data lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 6 GO:0098772 molecular function regulator activity 3
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 1
Pathway
R-HSA-9748784 Drug ADME 8 R-HSA-1430728 Metabolism 5 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 2
Partners
HNF4ANR1H4NR1I2PPARARELARXRASRC1
Complex memberships
CAR/RXRα heterodimer

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 NR1I3 (MB67) was identified as an orphan nuclear hormone receptor predominantly expressed in liver that binds and transactivates retinoic acid response elements (DR5 motifs) as a heterodimer with RXR, exhibiting constitutive (ligand-independent) transactivation activity dependent on the AF-2 motif. Receptor cloning, gel shift assays, transient transfection/reporter assays, RXR heterodimerization studies Molecular and cellular biology High 8114692
1997 NR1I3 (hCAR/mCAR) acts as a constitutive transcriptional activator that heterodimerizes with RXR to bind retinoic acid response elements; a truncated splice variant mCAR2 lacking part of the ligand-binding/dimerization domain fails to bind DNA or transactivate, and also cannot inhibit mCAR1/hCAR activity. Gene cloning, transient transfection reporter assays, gel shift/DNA binding assays, dominant-negative analysis The Journal of biological chemistry High 9295294
1998 CAR-beta (NR1I3) constitutive transcriptional activity results from ligand-independent recruitment of transcriptional co-activators; androstanol and androstenol (3α-hydroxy, 5α-reduced androstanes) function as inverse agonists by promoting co-activator release from the ligand-binding domain without affecting heterodimerization or DNA binding, defining a class of naturally occurring nuclear receptor inverse agonists. In vitro transcription/reporter assays, ligand-binding studies, co-activator interaction assays, steroid structure-activity analysis Nature High 9783588
2000 CAR (NR1I3) can activate CYP3A genes through PXR/SXR response elements, and conversely PXR/SXR can activate CYP2B genes through the phenobarbital response element (PBRE), demonstrating cross-regulatory overlap between these two xenobiotic receptors in regulating multiple CYP gene classes. Cell-based reporter assays, transgenic mouse studies, gene expression analysis Genes & development High 11114890
2002 CAR (NR1I3) regulates acetaminophen metabolism and hepatotoxicity by inducing expression of three acetaminophen-metabolizing enzymes (including CYP enzymes); CAR null mice are resistant to acetaminophen toxicity, and administration of the inverse agonist androstanol 1 hour after acetaminophen treatment blocked hepatotoxicity in wild-type but not CAR null mice. CAR knockout mouse studies, gene expression analysis, in vivo hepatotoxicity model, pharmacological inverse agonist administration Science High 12376703
2002 CAR (NR1I3) transcriptionally activates CYP3A4 through two high-affinity binding motifs located ~7720 and ~150 bp upstream of the transcription start site, requiring cooperativity between the proximal promoter and the distal xenobiotic-responsive enhancer module (XREM); these CAR response elements also mediate transactivation by PXR. Transient transfection reporter assays, gel shift assays, in vitro and in vivo CAR activation, primary human hepatocyte studies Molecular pharmacology High 12130689
2002 CAR (NR1I3) constitutively regulates CYP2C9 expression through a newly identified distal CAR-responsive enhancer (CAR-RE) located between -2900 and -2841 bp of the CYP2C9 promoter, containing two DR-5 nuclear receptor binding motifs that bind hCAR, mCAR, and human PXR. Transfection assays, gel shift assays, mRNA quantification in HepG2 cells Molecular pharmacology Medium 12181452
2003 CITCO was identified as the first selective human CAR agonist; it potently activates CAR (NR1I3) in a fluorescence-based assay, is selective over PXR and other nuclear receptors, induces CAR nuclear translocation, and induces the prototypical CAR target gene CYP2B6 in primary human hepatocytes. Using CITCO, CAR and PXR activators were shown to differentially regulate overlapping but distinct sets of drug-metabolizing enzyme genes. Fluorescence-based receptor activation assay, nuclear translocation assay, primary human hepatocyte gene expression profiling, selectivity panel against other nuclear receptors The Journal of biological chemistry High 12611900
2003 CAR (NR1I3) activates all five components of the bilirubin-clearance pathway in liver; this induction is absent in CAR null mice, is present in mice expressing human CAR, and CAR null mice are defective in clearing chronically elevated bilirubin. Bilirubin itself can directly activate CAR. CAR expression is very low in neonatal liver, suggesting its functional deficit contributes to neonatal jaundice. CAR knockout and humanized mouse models, gene expression analysis, bilirubin clearance assays, receptor activation assays Proceedings of the National Academy of Sciences of the United States of America High 12644704
2003 PXR and CAR (NR1I3) both induce specific UGT1A isoforms involved in estrogen, thyroxin, bilirubin, and carcinogen metabolism; transgenic mice expressing constitutively active human PXR show markedly increased UGT activity and steroid clearance, demonstrating that both receptors transduce phase I and phase II adaptive hepatic responses. Transgenic mouse studies, UGT activity assays, gene expression analysis Proceedings of the National Academy of Sciences of the United States of America High 12644700
2003 Functional and structural comparison of PXR (NR1I2) and CAR (NR1I3) reveals key differences in gene expression targets, ligand profiles in cell-based assays, and crystallographic/structural features, highlighting their distinct but overlapping physiological roles as xenosensors. Gene expression assays, cell-based ligand profiling, crystallographic and structural modeling analyses Biochimica et biophysica acta Medium 12573482
2004 The X-ray crystal structure of the human CAR (NR1I3)/RXRα heterodimer reveals that CAR contains a unique single-turn Helix X that restricts conformational freedom of the C-terminal AF2 helix, favoring the active (transcriptionally competent) state without ligand. Helix X and AF2 sit atop four amino acids shielding the CAR ligand-binding pocket. A fatty acid ligand was found in the RXRα binding pocket, and stabilizing interactions from the heterodimer interface hold RXRα in an active conformation, explaining ligand-independent constitutive activation. X-ray crystallography of CAR/RXRα heterodimer, structural analysis of ligand-binding pocket Molecular cell High 15610735
2004 CAR (NR1I3) and PXR both bind to an ER6 motif in the CYP3A5 promoter and transactivate CYP3A5 expression; rifampin induces CYP3A5 mRNA in human hepatocytes and intestinal biopsies via this mechanism, and hepatic PXR expression correlates with CYP3A5 mRNA levels. Reporter assays, gel shift/EMSA, RT-PCR in primary hepatocytes and intestinal biopsies, correlation analysis The Journal of biological chemistry Medium 15252010
2005 The human CAR splice variant CAR3 (NR1I3), which has a 5-amino acid insertion in the ligand-binding domain, is ligand-activated (not constitutively active); CITCO and clotrimazole act as activating ligands for CAR3 (clotrimazole is an inverse agonist for the reference CAR1). Transactivation by CAR3 requires its DNA-binding domain and AF-2 motif, is markedly enhanced by RXRα cotransfection through an RXR AF-2-dependent mechanism, and RXR augments CAR3 activity by facilitating coactivator (SRC-1) recruitment. Transient transfection reporter assays, mammalian two-hybrid assays, mutational analysis of AF-2 and DNA-binding domains, RXR cotransfection studies Molecular pharmacology High 16099843
2005 Chronic activation of CAR (NR1I3) causes hepatocarcinogenesis; CAR null mice are completely resistant to tumorigenic effects of chronic xenobiotic stress. In the acute xenobiotic response, CAR directly up-regulates Mdm2 expression, contributing to increased DNA replication and inhibition of p53-mediated apoptosis, linking chronic environmental stress to tumor formation via this specific molecular mechanism. CAR knockout mouse carcinogenesis model, acute xenobiotic stress experiments, Mdm2 expression analysis, apoptosis and DNA replication assays Molecular endocrinology High 15831521
2005 CAR (NR1I3) and PXR regulate CYP2C8 expression through a distal PXR/CAR-binding site in the CYP2C8 promoter; CITCO (CAR agonist) and rifampicin (PXR agonist) induce CYP2C8 through this site. Additional regulatory elements for glucocorticoid receptor (GR) and HNF4α were also identified in the CYP2C8 promoter. Reporter assays, gel shift assays, primary human hepatocyte induction studies Molecular pharmacology Medium 15933212
2004 IL-1β inhibits CAR (NR1I3) expression and CAR-mediated induction of drug-metabolizing genes (CYP2B6, CYP2C9, CYP3A4, UGT1A1, GSTA1, GSTA2, SLC21A6) in human hepatocytes via NF-κB p65 activation, which interferes with glucocorticoid receptor (GR)-mediated transactivation of the CAR promoter through its distal glucocorticoid response element; LPS and IL-1β inhibit dexamethasone-induced histone H4 acetylation at the proximal CAR promoter region, as shown by chromatin immunoprecipitation. Human hepatocyte culture, RT-PCR, transient transfection assays, chromatin immunoprecipitation (ChIP), NF-κB inhibitor and overexpression studies Hepatology High 15382119
2008 CAR (NR1I3) regulates serum triglyceride levels under metabolic stress; ob/ob mice crossed onto Car−/− background show completely normalized serum triglycerides, and Car−/− mice are protected from high-fat diet-induced hypertriglyceridemia. Pharmacological CAR activation with TCPOBOP increases serum triglycerides in a CAR-dependent manner. CAR activation suppresses PPARα expression and its target genes (Cyp4a14, CPT1α, CTE), and Car−/− animals exhibit increased hepatic fatty acid oxidation, indicating that CAR antagonizes PPARα-mediated fatty acid oxidation. Car knockout and ob/ob mouse genetic crosses, high-fat diet model, pharmacological CAR activation (TCPOBOP), PPARα target gene expression analysis, fatty acid oxidation assays Journal of lipid research High 18941143
2008 CAR (NR1I3) and PXR cross-talk with multiple hormone-responsive transcription factors (FoxO1, FoxA2, CREB, PGC-1α) to downregulate hepatic energy metabolism including gluconeogenesis, fatty acid oxidation, and ketogenesis while upregulating lipogenesis; CAR also modulates thyroid hormone activity by regulating type 1 deiodinase in the regenerating liver. Gene expression studies, nuclear receptor cross-talk assays, hepatic metabolic pathway analysis in rodent models Drug metabolism and pharmacokinetics Medium 18305370
2009 Retinoids (including all-trans retinoic acid and 9-cis retinoic acid) activate the RXRα/CAR (NR1I3)-mediated pathway and induce CYP3A gene expression; RXRα and CAR are recruited to both the proximal ER6 and distal XREM nuclear receptor response elements of the CYP3A4 gene promoter, as demonstrated by chromatin immunoprecipitation assay. Induction is preferentially mediated by RXRα/CAR and RXRγ/CAR heterodimers. Transient transfection assays in HepG2 cells, chromatin immunoprecipitation (ChIP), RT-PCR Biochemical pharmacology Medium 19686701
2013 NR1I3 gene polymorphisms are significantly associated with tacrolimus pharmacokinetics (dose-adjusted trough concentration) in liver transplant patients, indicating that NR1I3 variants influence tacrolimus metabolism in vivo in humans. Pharmacokinetic analysis in 96 liver transplant patients, genotyping of NR1I3 and CYP3A5 polymorphisms, multiple linear regression modeling Drug metabolism and pharmacokinetics Low 24351870
2014 CAR (NR1I3) can be activated by both direct ligand binding and ligand-independent (indirect) mechanisms; without activation, CAR forms a cytoplasmic protein complex. Indirect activation involves nuclear translocation through multiple signaling pathways including those affecting the cytoplasmic retention complex, while direct activation involves ligand binding followed by nuclear translocation. Both modes of activation converge on nuclear accumulation and target gene transactivation. Review synthesizing protein complex studies, nuclear translocation assays, signaling pathway inhibitor studies Protein & cell Medium 24474196
2018 Genome-wide characterization of CAR (NR1I3) binding in mouse liver after drug activation shows that CAR-linked genes are either stimulated or inhibited; stimulation but not inhibition correlates with increased H4K5 acetylation. Transcriptional inhibition occurs when CAR binds together with HNF4α, PPARα, or FXR on the same enhancers, where functional competition among co-bound nuclear receptors regulates metabolic gene expression. Drug-activated CAR displaces these endogenous metabolic regulators, constitutively altering metabolic gene regulation. ChIP-seq for CAR, RXRα, and H4K5Ac genome-wide in mouse liver; gene expression analysis iScience High 30396153
2021 In human liver cancer, CAR (NR1I3) plays a tumor-suppressive role distinct from its pro-tumorigenic role in rodent models; CAR drives differentiation and liver regeneration and regulates liver cancer stem cells in human hepatocytes. Species differences in CAR activity mean that the rodent liver tumorigenesis mechanism is not applicable to humans. Review of human hepatocyte studies, liver cancer models; primary CAR activation/loss-of-function experiments in human liver cancer cells Biochimica et biophysica acta. Reviews on cancer Low 33529650

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2014 An atlas of genetic influences on human blood metabolites. Nature genetics 1209 24816252
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2017 Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science (New York, N.Y.) 934 28473536
2012 Quantitative analysis of HSP90-client interactions reveals principles of substrate recognition. Cell 708 22939624
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2022 CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. Journal of experimental & clinical cancer research : CR 520 35361234
1996 An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science (New York, N.Y.) 441 8650544
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2019 An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. American journal of hematology 411 30680780
2019 Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells. International journal of molecular sciences 408 30875739
2017 Engineering CAR-T cells. Biomarker research 408 28652918
1998 Androstane metabolites bind to and deactivate the nuclear receptor CAR-beta. Nature 405 9783588
2002 PXR, CAR and drug metabolism. Nature reviews. Drug discovery 400 12120277
2000 Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes & development 391 11114890
1994 A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Molecular and cellular biology 389 8114692
2003 Identification of a novel human constitutive androstane receptor (CAR) agonist and its use in the identification of CAR target genes. The Journal of biological chemistry 348 12611900
2021 An NK-like CAR T cell transition in CAR T cell dysfunction. Cell 314 34861191
2003 Induction of bilirubin clearance by the constitutive androstane receptor (CAR). Proceedings of the National Academy of Sciences of the United States of America 288 12644704
2003 Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proceedings of the National Academy of Sciences of the United States of America 272 12644700
2002 Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science (New York, N.Y.) 250 12376703
2005 Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Molecular endocrinology (Baltimore, Md.) 245 15831521
2024 CAR-T and CAR-NK as cellular cancer immunotherapy for solid tumors. Cellular & molecular immunology 229 39134804
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
1997 Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. The Journal of biological chemistry 218 9295294
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
2022 Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy. Nature medicine 204 36097223
2009 PXR and CAR in energy metabolism. Trends in endocrinology and metabolism: TEM 199 19595610
2012 Role of CAR and PXR in xenobiotic sensing and metabolism. Expert opinion on drug metabolism & toxicology 190 22554043
2002 Transcriptional regulation of the human CYP3A4 gene by the constitutive androstane receptor. Molecular pharmacology 188 12130689
2020 Gamma-Delta CAR-T Cells Show CAR-Directed and Independent Activity Against Leukemia. Frontiers in immunology 187 32714329
2004 A structural basis for constitutive activity in the human CAR/RXRalpha heterodimer. Molecular cell 178 15610735
2023 CAR-T: What Is Next? Cancers 173 36765623
2004 The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR). The Journal of biological chemistry 162 15252010
2019 Target selection for CAR-T therapy. Journal of hematology & oncology 157 31221182
2005 Human CYP2C8 is transcriptionally regulated by the nuclear receptors constitutive androstane receptor, pregnane X receptor, glucocorticoid receptor, and hepatic nuclear factor 4alpha. Molecular pharmacology 153 15933212
2016 CAR models: next-generation CAR modifications for enhanced T-cell function. Molecular therapy oncolytics 137 27231717
2023 Forks in the road for CAR T and CAR NK cell cancer therapies. Nature immunology 134 38012406
1991 Gene targeting of the aggregation stage cAMP receptor cAR1 in Dictyostelium. Genes & development 134 1849108
2021 Counteracting CAR T cell dysfunction. Oncogene 129 33168929
2004 Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance. Hepatology (Baltimore, Md.) 128 15382119
2002 Regulation of human CYP2C9 by the constitutive androstane receptor: discovery of a new distal binding site. Molecular pharmacology 127 12181452
2021 Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. Science signaling 125 34429382
2018 Chimeric Antigen Receptor (CAR) Treg: A Promising Approach to Inducing Immunological Tolerance. Frontiers in immunology 123 30369931
2012 Targeting xenobiotic receptors PXR and CAR for metabolic diseases. Trends in pharmacological sciences 121 22889594
2008 Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways. Pharmaceutical research 121 19034627
2022 3D-organoid culture supports differentiation of human CAR+ iPSCs into highly functional CAR T cells. Cell stem cell 116 35278370
2008 The roles of nuclear receptors CAR and PXR in hepatic energy metabolism. Drug metabolism and pharmacokinetics 116 18305370
2012 Ancestral capture of syncytin-Car1, a fusogenic endogenous retroviral envelope gene involved in placentation and conserved in Carnivora. Proceedings of the National Academy of Sciences of the United States of America 105 22308384
2022 CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications. Biomedicines 100 35203496
2003 Functional and structural comparison of PXR and CAR. Biochimica et biophysica acta 100 12573482
2021 From CAR-T Cells to CAR-NK Cells: A Developing Immunotherapy Method for Hematological Malignancies. Frontiers in oncology 95 34422667
2014 CD19-CAR trials. Cancer journal (Sudbury, Mass.) 94 24667955
2008 The nuclear receptor CAR (NR1I3) regulates serum triglyceride levels under conditions of metabolic stress. Journal of lipid research 92 18941143
2014 Signaling control of the constitutive androstane receptor (CAR). Protein & cell 88 24474196
2022 CAR-Macrophages and CAR-T Cells Synergistically Kill Tumor Cells In Vitro. Cells 79 36429120
2018 Glycan-directed CAR-T cells. Glycobiology 78 29370379
2022 CAR density influences antitumoral efficacy of BCMA CAR T cells and correlates with clinical outcome. Science advances 75 36179026
2017 Regional Delivery of Chimeric Antigen Receptor (CAR) T-Cells for Cancer Therapy. Cancers 75 28718815
2016 Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells. Cytotherapy 72 27592405
2024 Indolent CD4+ CAR T-Cell Lymphoma after Cilta-cel CAR T-Cell Therapy. The New England journal of medicine 71 38865661
2005 Retinoid X receptor-alpha-dependent transactivation by a naturally occurring structural variant of human constitutive androstane receptor (NR1I3). Molecular pharmacology 71 16099843
2021 Insight into next-generation CAR therapeutics: designing CAR T cells to improve clinical outcomes. The Journal of clinical investigation 70 33463538
2017 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Thoracic Malignancies. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 69 29107016
2019 A Metabolism Toolbox for CAR T Therapy. Frontiers in oncology 59 31114756
2016 Small-molecule modulators of PXR and CAR. Biochimica et biophysica acta 59 26921498
2023 Trogocytosis of CAR molecule regulates CAR-T cell dysfunction and tumor antigen escape. Signal transduction and targeted therapy 56 38143263
2023 Harnessing CD3 diversity to optimize CAR T cells. Nature immunology 55 37932456
2023 Non-viral chimeric antigen receptor (CAR) T cells going viral. Immuno-oncology technology 53 37124148
2022 Novel insights in CAR-NK cells beyond CAR-T cell technology; promising advantages. International immunopharmacology 51 35149294
2016 Chimeric Antigen Receptor (CAR) therapy for multiple myeloma. British journal of haematology 50 26791002
2023 Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy. Frontiers in immunology 49 37205115
2005 What does it take to bind CAR? Molecular therapy : the journal of the American Society of Gene Therapy 47 16109509
2025 In vivo CAR engineering for immunotherapy. Nature reviews. Immunology 45 40379910
2019 Treating osteosarcoma with CAR T cells. Scandinavian journal of immunology 44 30549299
2023 ALK inhibitors increase ALK expression and sensitize neuroblastoma cells to ALK.CAR-T cells. Cancer cell 39 38039964
2023 AhR, PXR and CAR: From Xenobiotic Receptors to Metabolic Sensors. Cells 39 38067179
2020 CAR T and CAR NK cells in multiple myeloma: Expanding the targets. Best practice & research. Clinical haematology 38 32139020
2009 Retinoids activate RXR/CAR-mediated pathway and induce CYP3A. Biochemical pharmacology 38 19686701
2003 Adenovirus interaction with its cellular receptor CAR. Current topics in microbiology and immunology 38 12747555
2022 Special Chimeric Antigen Receptor (CAR) Modifications of T Cells: A Review. Frontiers in oncology 37 35392217
2021 NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development. Cells 37 34943898
2017 CAR: A key regulator of adhesion and inflammation. The international journal of biochemistry & cell biology 37 28545889
1995 Agonist-induced loss of ligand binding is correlated with phosphorylation of cAR1, a G protein-coupled chemoattractant receptor from Dictyostelium. The Journal of biological chemistry 37 7721769
2023 CAR-T-Derived Extracellular Vesicles: A Promising Development of CAR-T Anti-Tumor Therapy. Cancers 36 36831396
2020 Challenges of CAR- and TCR-T cell-based therapy for chronic infections. The Journal of experimental medicine 36 32163104
2013 An update on the constitutive androstane receptor (CAR). Drug metabolism and drug interactions 34 23729557
2023 Site-specific transgene integration in chimeric antigen receptor (CAR) T cell therapies. Biomarker research 32 37403182
2019 CAR T Cells: A Snapshot on the Growing Options to Design a CAR. HemaSphere 32 31723811
2018 The development of CAR design for tumor CAR-T cell therapy. Oncotarget 32 29568411
2011 Constitutive androstane receptor (CAR) is a xenosensor and target for therapy. Biochemistry. Biokhimiia 31 22098234
2025 Engineering sonogenetic EchoBack-CAR T cells. Cell 30 40179881
2020 Revving the CAR - Combination strategies to enhance CAR T cell effectiveness. Blood reviews 29 32402724
1996 The cell density factor CMF regulates the chemoattractant receptor cAR1 in Dictyostelium. The Journal of cell biology 29 8830781
2024 A CAR enhancer increases the activity and persistence of CAR T cells. Nature biotechnology 28 39079964
2020 CAR T-Cells. Advances in experimental medicine and biology 28 32301017
2025 CAR T cells, CAR NK cells, and CAR macrophages exhibit distinct traits in glioma models but are similarly enhanced when combined with cytokines. Cell reports. Medicine 26 39889712
2024 CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar. Biomolecules & biomedicine 26 37877819
2024 Redirecting B7-H3.CAR T Cells to Chemokines Expressed in Osteosarcoma Enhances Homing and Antitumor Activity in Preclinical Models. Clinical cancer research : an official journal of the American Association for Cancer Research 25 39101835
2020 CAR T-cells profiling in carcinogenesis and tumorigenesis: An overview of CAR T-cells cancer therapy. International immunopharmacology 24 33249047
2019 The making and function of CAR cells. Immunology letters 24 31181279
2018 GITR domain inside CAR co-stimulates activity of CAR-T cells against cancer. Frontiers in bioscience (Landmark edition) 24 29772559
2013 Association of hemoglobin levels, CYP3A5, and NR1I3 gene polymorphisms with tacrolimus pharmacokinetics in liver transplant patients. Drug metabolism and pharmacokinetics 24 24351870
2023 Advancing CAR-based immunotherapies in solid tumors: CAR- macrophages and neutrophils. Frontiers in immunology 23 38090576
2019 CAR Talk: How Cancer-Specific CAR T Cells Can Instruct How to Build CAR T Cells to Cure HIV. Frontiers in immunology 23 31611880
2005 Beyond CAR and PXR. Current drug metabolism 23 16101576
2023 CAR T cell therapy becomes CHIC: "cytokine help intensified CAR" T cells. Frontiers in immunology 22 36700225
2022 Lenalidomide enhances CD23.CAR T cell therapy in chronic lymphocytic leukemia. Leukemia & lymphoma 22 35259043
2024 CAR T cells outperform CAR NK cells in CAR-mediated effector functions in head-to-head comparison. Experimental hematology & oncology 21 38745250
2018 Binding of Drug-Activated CAR/Nr1i3 Alters Metabolic Regulation in the Liver. iScience 21 30396153
2022 Synthetic Biology in Chimeric Antigen Receptor T (CAR T) Cell Engineering. ACS synthetic biology 20 35005887
2021 Role of the constitutive androstane receptor (CAR) in human liver cancer. Biochimica et biophysica acta. Reviews on cancer 20 33529650
2023 Infectious complications of chimeric antigen receptor (CAR) T-cell therapies. Seminars in hematology 19 37080711
2023 The physical landscape of CAR-T synapse. Biophysical journal 19 37715447
2021 Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma. Pharmacology & therapeutics 19 34582835
2016 Minicircle-Based Engineering of Chimeric Antigen Receptor (CAR) T Cells. Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 19 28101686
2021 Novel progresses of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma. Stem cell investigation 18 33575314
2021 Engineering Metabolism of Chimeric Antigen Receptor (CAR) Cells for Developing Efficient Immunotherapies. Cancers 18 33807867
2023 Rational Protein Design Yields a CD20 CAR with Superior Antitumor Efficacy Compared with CD19 CAR. Cancer immunology research 17 36409926
2021 The Race of CAR Therapies: CAR-NK Cells for Fighting B-Cell Hematological Cancers. Cancers 17 34771581
2019 The promise of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma. Cellular immunology 17 31492448
2024 Beyond CAR T cells: exploring alternative cell sources for CAR-like cellular therapies. Biological chemistry 16 38766710
2024 Universal CAR 2.0 to overcome current limitations in CAR therapy. Frontiers in immunology 16 38962014
2024 Armoring chimeric antigen receptor (CAR) T cells as micropharmacies for cancer therapy. Immuno-oncology technology 16 39711794
2022 Joining Forces for Cancer Treatment: From "TCR versus CAR" to "TCR and CAR". International journal of molecular sciences 16 36498890
2023 Building safety into CAR-T therapy. Human vaccines & immunotherapeutics 15 37968136
2021 Chimeric antigen receptor (CAR) immunotherapy: basic principles, current advances, and future prospects in neuro-oncology. Immunologic research 15 34554405