Affinage

IL4I1

L-amino-acid oxidase · UniProt Q96RQ9

Length
567 aa
Mass
62.9 kDa
Annotated
2026-06-10
69 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL4I1 is a secreted FAD-dependent L-amino acid oxidase, expressed by myeloid antigen-presenting cells and IL-4-stimulated B cells, that functions as a metabolic immune checkpoint converting aromatic amino acids into immunomodulatory products (PMID:17356132, PMID:32818467). First identified as the immediate-early IL-4-inducible B-cell gene Fig1 encoding a flavoprotein with monoamine oxidase/L-amino acid oxidase homology (PMID:9122225, PMID:9703950, PMID:12031486), the enzyme was shown to be optimally active toward L-phenylalanine at physiological pH (with secondary activity on tryptophan and arginine) and to produce H2O2 as a catabolite; naturally occurring variants confirm exon-4 residues as catalytically critical (PMID:17356132, PMID:26673964). Through H2O2 production, phenylalanine depletion, and transient TCRζ downregulation, IL4I1 inhibits CD3-stimulated CD4+ and CD8+ T-cell proliferation, suppresses IFN-γ production, inhibits mTORC1 signaling, destabilizes the T cell–DC immune synapse, and promotes FoxP3+ Treg differentiation (PMID:17356132, PMID:25778793, PMID:33343572). From tryptophan, IL4I1 generates indole metabolites — indole-3-pyruvate (I3P), indole-3-aldehyde/IAld, indole-3-acetic acid, and kynurenic acid — that activate the aryl hydrocarbon receptor (AHR) to drive immunosuppression across diverse tumor entities more frequently than IDO1 or TDO2 (PMID:32818467, PMID:32866000, PMID:37507432). Independently of AHR, the I3P metabolite blocks ferroptosis by direct free-radical scavenging and by stabilizing NRF2 (via reduced ubiquitination) to restore an antioxidant program, an activity that underlies pro-tumorigenic and cytoprotective effects in glioblastoma, neuroblastoma, and post-infarct myocardium (PMID:33646117, PMID:40907328, PMID:40071723, PMID:42176266). In vivo, IL4I1 restrains antitumor CD8+ T-cell responses, drives macrophage M2 polarization, and promotes tumor immune escape, and macrophage-specific deletion or small-molecule inhibition restores antitumor immunity (PMID:21469114, PMID:26599209, PMID:41537775, PMID:42252303). IL4I1 transcription is induced by NF-κB and STAT1 in myeloid cells and the IL-4/STAT6 axis in B cells, antagonistically regulated by p53, and modulated by SP1 under mechanical stress and by JMJD3-mediated histone demethylation (PMID:20683900, PMID:30419821, PMID:36537648, PMID:37478857). IL4I1 also binds the immune-cell surface protein TMPRSS13 (PMID:36131918).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1997 Medium

    Established IL4I1 as an IL-4-inducible B-cell gene whose sequence predicted a flavoenzyme, framing the question of its catalytic identity.

    Evidence cDNA representational difference analysis and sequence/FAD-domain analysis in B cells

    PMID:9122225

    Open questions at the time
    • Enzymatic activity not demonstrated
    • Substrate unknown
    • Cellular function undefined
  2. 2002 Medium

    Sequence and structural-homology mapping to the L-amino acid oxidase crystal structure predicted conserved catalytic and FAD-binding residues, narrowing the enzyme to the LAAO family.

    Evidence Genomic cloning and homology mapping of human and mouse orthologs

    PMID:12031486 PMID:9703950

    Open questions at the time
    • Predicted residues not yet mutationally validated
    • No direct enzymatic measurement
  3. 2007 High

    Demonstrated that IL4I1 is a secreted L-phenylalanine oxidase producing H2O2 and that its enzymatic activity is required to suppress T-cell proliferation, establishing the core immunoregulatory mechanism.

    Evidence Stable HEK293 expression, enzymatic and H2O2 assays, T-cell proliferation with enzymatic blockade

    PMID:17356132

    Open questions at the time
    • TCRζ downregulation mechanism not fully resolved
    • In vivo relevance not yet shown
  4. 2010 Medium

    Defined the transcriptional control of IL4I1 — NF-κB/STAT1 in myeloid cells versus NF-κB and IL-4/STAT6 in B cells — explaining cell-type-specific induction.

    Evidence In vitro stimulation with pathway inhibitors/activators and T-cell proliferation readouts

    PMID:20683900

    Open questions at the time
    • Direct promoter occupancy not mapped here
    • Quantitative contribution of each pathway unresolved
  5. 2011 High

    Showed in vivo that IL4I1 suppresses the CD8+ antitumor response, moving the enzyme from in vitro suppressor to a driver of tumor immune escape.

    Evidence Mouse melanoma model co-expressing IL4I1 and GP33 with vaccination and IFN-γ+ CD8 readouts

    PMID:21469114

    Open questions at the time
    • Metabolite mediators not yet identified
    • Mechanism of CD8 reduction not dissected
  6. 2013 Medium

    Extended IL4I1 function to antibacterial defense, showing H2O2, ammonia-driven basification, and phenylalanine depletion as effector mechanisms.

    Evidence In vitro and in vivo bacterial growth assays with catalase neutralization

    PMID:23355881

    Open questions at the time
    • Relative in vivo contributions context-dependent
    • Single lab
  7. 2015 Medium

    Connected IL4I1 catabolism to T-cell fate (Treg enrichment via phenylalanine consumption and mTORC1 inhibition), to M2 macrophage polarization, and broadened the substrate range to arginine; gain/loss variants confirmed active-site residues.

    Evidence T-cell differentiation, Phe-deprivation, mTORC1 assays, BMDM polarization, enzymatic variant assays, sperm LAAO localization

    PMID:25767141 PMID:25778793 PMID:26599209 PMID:26673964

    Open questions at the time
    • Tryptophan metabolite identity not yet defined
    • Mechanism linking metabolism to STAT3/6 activation unclear
  8. 2016 High

    Genetic KO and recombinant rescue established a tissue-protective role in CNS, with IL4I1 limiting proinflammatory macrophages and supporting remyelination.

    Evidence IL4I1-knockout mice, focal demyelination, recombinant protein rescue, EAE model

    PMID:27797811

    Open questions at the time
    • Metabolite mediator not identified
    • Direct vs. indirect macrophage effects unresolved
  9. 2018 Medium

    Identified antagonistic NF-κB/p53 co-regulation of IL4I1 under ionizing radiation, adding a stress-responsive layer to its transcriptional control.

    Evidence RNA-seq with TP53/RELA silencing and ChIP-seq in irradiated U2-OS cells

    PMID:30419821

    Open questions at the time
    • Functional consequence of radiation-induced IL4I1 not tested
    • Single cell line
  10. 2020 High

    Revealed the dominant tryptophan-to-indole/kynurenic acid axis driving AHR activation across cancers and showed IL4I1 operates independently of IDO1, redefining it as a pan-cancer AHR-activating immune checkpoint.

    Evidence Pan-tumor AHR signature, metabolite profiling, mouse CLL model, IDO1 inhibitor experiments, DC CYP1A1 readouts

    PMID:32818467 PMID:32866000

    Open questions at the time
    • Receptor/uptake of metabolites by AHR-expressing cells not fully mapped
    • Relative weighting of H2O2 vs. indole signaling unresolved
  11. 2020 High

    Genetic KO during acute infection showed a context-dependent role: IL4I1 accelerates effector CD8 expansion and tunes TCR affinity while restraining memory precursors and destabilizing immune synapses.

    Evidence IL4I1-deficient mice, acute LCMV infection, TCR clone tracking, in vitro synapse stability assay

    PMID:33343572

    Open questions at the time
    • Molecular basis of synapse destabilization unresolved
    • Reconciliation with suppressive role context-specific
  12. 2021 High

    Distinguished mammalian IL4I1 from cytotoxic snake-venom LAAO by identifying I3P as the product that suppresses ferroptosis via radical scavenging and antioxidant gene induction, proposing this as the pro-tumorigenic mechanism.

    Evidence Recombinant IL4I1 vs. venom LAAO, ferroptosis assays, I3P treatment, gene profiling

    PMID:33646117

    Open questions at the time
    • AHR-dependence of antioxidant program not yet separated
    • Direct molecular target of I3P not defined here
  13. 2022 Medium

    Added regulatory and interaction detail: TMPRSS13 surface binding, JAK/STAT-mediated PD-L1 upregulation, and JMJD3/histone-demethylation control of IL4I1 transcription.

    Evidence Pulldown/competition assays, siRNA with JAK/STAT rescue, ChIP and inhibitor experiments in macrophage/lung models

    PMID:36056935 PMID:36131918 PMID:36537648

    Open questions at the time
    • Functional consequence of TMPRSS13 binding for signaling unclear
    • Reciprocal validation of the interaction limited
  14. 2023 Medium

    Showed IL4I1 indole-AHR signaling operates beyond cancer immunity — in muscle stem cell anti-inflammation, decidualization, and mechanical-stress-driven thermal resistance — and is induced by SP1 under confinement.

    Evidence MuSC priming, hCG/endometrial decidualization assays, 3D bioprinting thermal ablation with SP1 manipulation and AHR inhibition

    PMID:36834576 PMID:37478857 PMID:37507432

    Open questions at the time
    • Generality across tissues untested
    • Each pathway from single lab
  15. 2024 Medium

    Demonstrated MSC-secreted IL4I1 as a required effector of therapeutic Th1 suppression in lupus nephritis, and kynurenic acid as a metabolite driving CAR-T exhaustion via AHR.

    Evidence IL4I1 genetic ablation in hUC-MSCs in LN model; 3D collagen integrin αvβ1–IL4I1–KynA–AHR chain with CAR-T co-culture

    PMID:39216468 PMID:39557841

    Open questions at the time
    • Direct metabolite measurement in MSC setting limited
    • Relative contribution of KynA vs. I3P to T-cell suppression unclear
  16. 2025 High

    Resolved a key mechanistic question by showing I3P directly binds NRF2 and reduces its ubiquitination to block ferroptosis independently of AHR, while AHR→NRF2 also operates in macrophages; additional signaling effects (AKT/FOXO1, JAK2/STAT3) were linked to Th17 and EMT phenotypes.

    Evidence I3P-NRF2 binding/ubiquitination assays with AHR inhibitor controls, NRF2 KD, macrophage MI model, AKT/FOXO1 and JAK2/STAT3 pathway manipulation, xenografts

    PMID:40071723 PMID:40353627 PMID:40769409 PMID:40907328

    Open questions at the time
    • Structural basis of I3P-NRF2 binding not solved
    • Crosstalk between AHR-dependent and -independent NRF2 routes unresolved
  17. 2026 High

    Cell-type-specific deletion, autochthonous cancer models, and a selective small-molecule inhibitor established IL4I1 as a tractable therapeutic target whose catalytic blockade restores antitumor immunity and re-sensitizes tumors to ferroptosis.

    Evidence Macrophage-specific conditional KO in melanoma, IL4i1-KO neuroblastoma model, ZY-MY-111 enzymatic inhibition and syngeneic tumor efficacy

    PMID:41537775 PMID:42176266 PMID:42252303

    Open questions at the time
    • Clinical translation untested
    • Selectivity and pharmacodynamics of inhibitors require further definition

Open questions

Synthesis pass · forward-looking unresolved questions
  • How IL4I1's parallel outputs — H2O2, amino acid depletion, AHR-activating indoles/kynurenic acid, and AHR-independent NRF2 stabilization — are integrated and prioritized in a given cell or tissue context remains unresolved.
  • No structural model integrating substrate/product flux with downstream signaling
  • Quantitative contribution of each effector arm in vivo undefined
  • Functional role of TMPRSS13 binding for IL4I1 signaling unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 5 GO:0140098 catalytic activity, acting on RNA 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-168256 Immune System 5 R-HSA-1430728 Metabolism 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3
Partners
TMPRSS13

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 IL4I1 (Fig1) was identified as the first characterized immediate-early IL-4-inducible gene from B cells. The Fig1 cDNA encodes a predicted 70-kDa flavoprotein with homology to monoamine oxidases, particularly in FAD-binding domains, suggesting it is a flavoenzyme. cDNA representational difference analysis (RDA subtraction), sequence analysis Proceedings of the National Academy of Sciences of the United States of America Medium 9122225
1998 The mouse IL4I1 (Fig1) protein shows 37% identity to snake venom L-amino acid oxidase, establishing it as a member of the L-amino acid oxidase (LAAO) family and predicting its enzymatic function. cDNA sequencing, protein sequence similarity search Biochemical and biophysical research communications Medium 9703950
2002 Human IL4I1 (hFig1) has the same 8-exon genomic structure as mouse Fig1, encodes a predicted 63-kDa secreted protein with L-amino acid oxidase homology (43% identity over 484 aa), conserves key catalytic residues and FAD-binding residues identified in the LAAO crystal structure, and is induced by IL-4 in B lymphocytes. Genomic cloning, sequence analysis, structural homology mapping to LAAO crystal structure Biochimica et biophysica acta Medium 12031486
2007 Human IL4I1 is a secreted L-amino acid oxidase with activity optimally directed toward L-phenylalanine at physiological pH. The enzyme produces H2O2 as a catabolite. IL4I1 inhibits CD3-stimulated T-lymphocyte proliferation (both CD4+ and CD8+) in a manner dependent on enzymatic activity and H2O2 production, and is associated with transient TCRζ downregulation. The enzyme is most functionally active in mature dendritic cells. Stable HEK293 transfection, enzymatic activity assays, T-cell proliferation assays, blocking experiments, immunohistochemistry, flow cytometry Blood High 17356132
2010 IL4I1 expression in mononuclear phagocytes (macrophages and dendritic cells) is induced by pro-inflammatory stimuli through activation of transcription factors NF-κB and/or STAT1. In B cells, IL4I1 expression is induced by NF-κB-activating stimuli (e.g., CD40L) and the IL-4/STAT6 axis, but B cells are insensitive to IFN-γ, unlike myeloid cells. IL4I1 expression by a monocytic cell line inhibits T-cell proliferation and IFN-γ production. In vitro stimulation assays, transcription factor pathway inhibitors/activators, T-cell proliferation assays European journal of immunology Medium 20683900
2011 IL4I1 inhibits the CD8+ antitumor T-cell response in vivo. In a mouse melanoma model constitutively co-expressing IL4I1 and the GP33 epitope, tumors developed more frequently after GP33 vaccination, preceded by rapid reduction of IFN-γ-producing cytotoxic CD8+ T cells. Mouse tumor model, GP33 vaccination, flow cytometry for IFN-γ-producing CD8+ T cells, tumor incidence monitoring European journal of immunology High 21469114
2013 IL4I1 exerts antibacterial activity by blocking growth of both Gram-negative and Gram-positive bacteria in vitro and in vivo, primarily through H2O2 production, amplified by medium basification from ammonia accumulation. Phenylalanine depletion also contributes to in vivo inhibition of staphylococci. In vitro bacterial growth assays, in vivo infection models, H2O2 measurement, catalase neutralization experiments PloS one Medium 23355881
2015 IL4I1 promotes FoxP3+ regulatory T (Treg) cell differentiation from naïve CD4+ T cells in vitro (human and mouse) while limiting Th1 and Th2 polarization and modifying the Th17 phenotype. Phenylalanine consumption by IL4I1 participates in Treg enrichment, and IL4I1 inhibits mTORC1 signaling shortly after T-cell activation. In vitro T-cell differentiation assays, phenylalanine deprivation experiments, H2O2 addition experiments, mTORC1 activity assays, IL4I1 from multiple sources tested European journal of immunology Medium 25778793
2015 IL4I1 has L-amino acid oxidase activity directed against arginine in addition to phenylalanine (primary substrate). Two naturally occurring variants alter activity: the N92D SNP yields a hyperactive enzyme and the R102G mutation yields a hypomorphic enzyme, confirming that exon 4 residues are critical for catalytic activity. Exogenous expression system, enzymatic activity assays with different amino acid substrates, site-specific variants Genes and immunity Medium 26673964
2015 IL4I1 drives macrophage polarization toward the M2 phenotype (increased Fizz1, Arg1, YM-1, MR expression), with IL4I1 overexpression activating STAT-3 and STAT-6 phosphorylation. IL4I1-produced macrophages inhibit T-cell activation through L-tryptophan catabolism, H2O2 production (blocked by DPI), IL-10 signaling (blocked by anti-IL-10Rα), and arginine catabolism (blocked by L-NMMA). BMDM differentiation, siRNA knockdown, overexpression, gene expression profiling, T-cell activation assays, pharmacological inhibitors, STAT phosphorylation assays PloS one Medium 26599209
2015 Human spermatozoa express IL4I1 LAAO activity with preferred substrates phenylalanine and tryptophan. The enzyme is localized to the acrosomal region and midpiece. Stimulation of LAAO activity induces hallmarks of sperm capacitation (tyrosine phosphorylation of flagellum, phospho-SRC activation) and acrosomal exocytosis via H2O2-dependent mechanisms reversible by catalase. LAAO enzymatic activity assays, immunolocalization, flow cytometry, tyrosine phosphorylation assays, catalase rescue experiments Reproduction (Cambridge, England) Medium 25767141
2016 IL4I1 modulates CNS inflammation and promotes remyelination by reducing interferon-γ and IL-17 expression in activated T cells; it does not directly affect oligodendrocyte differentiation. IL4I1-deficient mice show increased proinflammatory macrophage density and impaired remyelination after lysolecithin-induced focal demyelination. Recombinant IL4I1 administration into CNS lesions rescues remyelination impairment in IL4Rα-deficient mice and reduces proinflammatory macrophage density. IL4I1 knockout mice, focal demyelination model, recombinant IL4I1 injection, splenocyte culture assays, EAE model with IL4I1 IV injection, histological analysis Brain : a journal of neurology High 27797811
2020 IL4I1 generates indole metabolites (including indole-3-pyruvate, I3P) and kynurenic acid from tryptophan, and activates the aryl hydrocarbon receptor (AHR). Across 32 tumor entities, IL4I1 associates more frequently with AHR activity than IDO1 or TDO2. IL4I1 promotes cancer cell motility and suppresses adaptive immunity, enhancing CLL progression in mice. ICB induces IL4I1, and IDO1 inhibitors do not block IL4I1. Pan-tissue AHR signature (NLP), metabolite profiling, mouse CLL model, cell motility assays, immune assays, IDO1 inhibitor experiments Cell High 32818467
2020 IL4I1 catalyzes the indole pyruvate pathway in host cells, converting L-tryptophan to indole-3-acetic acid (IAA) and indole-3-carboxaldehyde (IAld), which accumulate in dendritic cells and stimulate CYP1A1 expression (an AHR target gene). IL4I1-overexpressing 293T cell line, metabolite measurement by mass spectrometry, CYP1A1 expression assays in dendritic cells Journal of agricultural and food chemistry Medium 32866000
2020 IL4I1 accelerates expansion of functional effector CD8+ T cells and increases average TCR affinity of the elicited repertoire during early LCMV infection, supporting more efficient viral clearance in WT vs. IL4I1-deficient mice. Conversely, IL4I1 restrains memory precursor differentiation and reduces the stability of T cell-DC immune synapses in vitro (increasing the threshold of T-cell activation), without affecting DC phenotype or antigen-presenting function. IL4I1-deficient mouse model, acute LCMV infection, transgenic CD8 T-cell clone tracking, in vitro immune synapse stability assay, flow cytometry Frontiers in immunology High 33343572
2021 Mammalian IL4I1 is non-cytotoxic (unlike snake venom LAAO) and instead produces indole-3-pyruvate (I3P) from tryptophan. I3P suppresses ferroptosis by direct free radical scavenging and by activating an anti-oxidative gene expression program. This anti-ferroptotic activity is proposed as the mechanism underlying IL4I1's pro-tumorigenic effects. Recombinant mammalian-expressed IL4I1 vs. snake venom LAAO, cell viability assays, ferroptosis induction, I3P treatment, gene expression profiling, free radical scavenging assays eLife High 33646117
2018 IL4I1 expression is co-regulated by NF-κB and p53 in cells exposed to ionizing radiation, with an antagonistic relationship: NF-κB activates and p53 inhibits IL4I1 transcription. Both p53 and RelA binding to putative regulatory regions of IL4I1 are enhanced by radiation. RNA-seq with TP53 and RELA silencing in irradiated U2-OS cells, ChIP-seq for p53 and RelA binding, qPCR validation BMC genomics Medium 30419821
2022 IL4I1 binds to transmembrane serine protease 13 (TMPRSS13), an immune cell-expressed surface protein. IL4I1 and SARS-CoV-2 spike share regions of homology and compete for TMPRSS13 binding. TMPRSS13 is expressed by human lymphocytes, monocytes, and macrophages, can cleave spike protein, and allows SARS-CoV-2 spike pseudotyped virus entry. Pulldown/binding assay, competition assay, TMPRSS13 overexpression, pseudotyped virus entry assay, flow cytometry for immune cell expression Frontiers in immunology Medium 36131918
2022 IL4I1 enhances PD-L1 expression in lung adenocarcinoma cells through the JAK/STAT signaling pathway. Silencing IL4I1 blocks JAK/STAT signaling and suppresses PD-L1 expression; this effect is reversed by the JAK/STAT activator RO8191. siRNA knockdown, Western blot for JAK/STAT pathway proteins and PD-L1, pharmacological rescue (RO8191), T cell cytotoxicity assay Immunogenetics Medium 36056935
2022 JMJD3 downregulates IL4I1 expression by demethylating H3K27me3 and H3K4me3 at the IL4I1 locus via a C/EBPβ-KDM5A linking mechanism. H3K4me3 demethylation at the IL4I1 locus inhibits IL4I1 transcription, increasing the M1/M2 macrophage ratio and aggravating LPS-induced acute lung injury. ChIP, siRNA/JMJD3 inhibitor (GSK-J4), in vivo ALI model, macrophage polarization assays, IL4I1 overexpression Environmental toxicology Medium 36537648
2023 IL4I1-produced indole metabolites I3P (indole-3-pyruvic acid) and I3A (indole-3-aldehyde) act as AHR ligands in cytokine-primed muscle stem cells, leading to increased TSG-6 expression and suppression of neutrophil infiltration. I3P also reduces ROS levels in neutrophils. IFN-γ/TNF-α priming of human MuSCs, IL4I1-dependent inhibition assays, I3P/I3A metabolite measurement, AHR activation assays, acute lung injury mouse model, neutrophil infiltration quantification Cell death discovery Medium 37507432
2023 Human chorionic gonadotropin (hCG) stimulates IL4I1 expression and secretion from endometrial epithelial cells through ornithine decarboxylase-induced putrescine production. IL4I1-catalyzed metabolites I3P and I3A from tryptophan induce human decidualization by activating AHR, which in turn upregulates Epiregulin as a downstream effector. Cell culture with hCG stimulation, ornithine decarboxylase inhibition, IL4I1 metabolite treatment (I3P, I3A), AHR reporter assays, Epiregulin expression measurement, in vitro decidualization assay International journal of molecular sciences Medium 36834576
2023 Mechanical confinement activates transcription factor SP1, which enhances IL4I1 transcription. IL4I1 then catalyzes tryptophan metabolites that activate AHR, leading to heat resistance in hepatocellular carcinoma cells. AHR inhibition prevents HCC recurrence after thermal ablation. 3D bioprinting-based thermal ablation system, SP1 manipulation, IL4I1 expression assays, tryptophan metabolite measurement, AHR inhibitor treatment, in vivo tumor recurrence model Cell reports. Medicine Medium 37478857
2024 IL4I1 is expressed in hUC-MSCs in response to the lupus nephritis (LN) kidney microenvironment. IL4I1 secretion by MSCs suppresses CXCR3+ Th1 cell infiltration into LN kidneys. Genetic ablation of IL4I1 in hUC-MSCs abolishes their therapeutic effects in LN. IL4I1 genetic ablation in hUC-MSCs, in vivo LN mouse model, single-cell RNA sequencing, Th1 cell infiltration quantification Signal transduction and targeted therapy Medium 39557841
2025 IL4I1-produced I3P activates AHR nuclear translocation and the NRF2 pathway in macrophages, suppressing reactive oxygen species, lipid peroxidation, and restoring FTH-1/GPX4 to inhibit ferroptosis. In IL4I1-KO mice post-MI, I3P administration rescues cardiac function impairments. This defines an IL4I1→I3P→AHR→NRF2→anti-ferroptosis cardioprotective axis. IL4I1 knockout mice, MI model, in vitro hypoxia-induced ferroptosis in macrophages, I3P treatment, AHR inhibitor, NRF2 pathway assays, lipid peroxidation and ROS measurements, I3P rescue in KO mice International immunopharmacology High 40907328
2025 IL4I1 inhibits Th17 cell differentiation by inactivating the AKT/FOXO1 signaling pathway. AKT activator SC79 reverses the suppressive effect of IL4I1 overexpression on Th17 cell differentiation. IL4I1 overexpression attenuates NAFLD progression in mice by reducing Th17 cells in liver. AAV8-mediated IL4I1 overexpression in mice, in vitro naive CD4+ T cell differentiation under Th17 conditions, IL4I1 KD, SC79 rescue, AKT/FOXO1 pathway protein measurement The Journal of biological chemistry Medium 40769409
2025 IL4I1 knockdown reverses the epithelial-mesenchymal transition (EMT) process in glioma cells, partially mediated through the JAK2/STAT3 signaling pathway. IL4I1 KD alters expression and localization of EMT-related biomarkers and suppresses glioma growth in xenograft models. siRNA knockdown, Western blot, immunofluorescence for EMT markers and JAK2/STAT3, xenograft tumor model Neoplasma Medium 40353627
2025 Tryptophan metabolite I3P produced by IL4I1 suppresses ferroptosis in glioblastoma by directly binding Nrf2 and reducing its ubiquitination, thereby stabilizing Nrf2. This anti-ferroptotic effect is AHR-independent. Nrf2 knockdown attenuates IL4I1-induced anti-ferroptosis, and IL4I1 OE with AHR inhibitor ML385 promotes ferroptosis in GBM xenografts. Transcriptomic analysis, I3P-Nrf2 binding assay, ubiquitination assay, Nrf2 knockdown, AHR inhibitor ML385, in vivo xenograft model Cell proliferation Medium 40071723
2026 Macrophage-specific IL4I1 deletion delayed tumor onset and metastatic dissemination in murine melanoma. Targeting IL4I1 restored antitumor TAM functions (increased antigen-presenting capacity) and restored proliferative and cytotoxic capacities of CD8+ T cells. TNFα, IL12, and IL1β coneutralization blocked IL4I1 upregulation in TAM subsets during melanoma progression. Macrophage-specific IL4I1 conditional knockout mice, murine melanoma models, chemical IL4I1 blockade, tumor growth and metastasis monitoring, T cell and macrophage functional assays Cancer immunology research High 41537775
2026 IL4i1 metabolites indole-3-pyruvate (I3P) and 4-hydroxyphenylpyruvate block ferroptosis in all human neuroblastoma cell lines via free radical scavenging and NRF2 activation, independently of the aryl hydrocarbon receptor. Supernatant transfer from IL4i1-expressing immune cells protects NB cells from oxidative death. IL4i1-knockout mice are protected from NB in a MYCN/mutant ALK-driven autochthonous cancer model. Recombinant IL4i1 protein, metabolite treatment, ferroptosis induction, NRF2 pathway assays, AHR knockout/inhibitor controls, supernatant transfer experiments, IL4i1-KO autochthonous mouse NB model Cell reports High 42176266
2026 ZY-MY-111, a selective small-molecule inhibitor of IL4I1, acts as a mixed-type inhibitor competitively occupying the catalytic pocket of IL4I1 (IC50 = 1.86 μM) and disrupting Trp-AHR signaling. In syngeneic tumor models, ZY-MY-111 inhibited tumor growth and remodeled the immunosuppressive microenvironment (increased CD8+/CD4+ T cell ratios, reduced MDSCs). In vitro enzymatic inhibition assay, kinetic analysis, cell-based Trp-AHR signaling assay, syngeneic CT26 colon carcinoma and A20 lymphoma mouse models, immune cell profiling Acta pharmacologica Sinica Medium 42252303
2024 In 3D collagen gels, integrin αvβ1 signaling increases IL4I1 expression in gastric cancer cells. IL4I1 metabolites, particularly kynurenic acid (KynA), promote CAR-T cell exhaustion by activating the AHR pathway, leading to decreased cytotoxicity. 3D collagen gel culture, co-culture with CAR-T cells, integrin αvβ1 blocking, IL4I1 metabolite measurement, AHR pathway assays, in vitro and in vivo cytotoxicity Translational oncology Medium 39216468

Source papers

Stage 0 corpus · 69 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression. Cell 449 32818467
2007 Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation. Blood 167 17356132
2021 Anti-ferroptotic mechanism of IL4i1-mediated amino acid metabolism. eLife 111 33646117
2015 IL4I1 Is a Novel Regulator of M2 Macrophage Polarization That Can Inhibit T Cell Activation via L-Tryptophan and Arginine Depletion and IL-10 Production. PloS one 106 26599209
2009 The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages. Leukemia 88 19436310
1997 Fig1, an interleukin 4-induced mouse B cell gene isolated by cDNA representational difference analysis. Proceedings of the National Academy of Sciences of the United States of America 86 9122225
2019 The IL4I1 Enzyme: A New Player in the Immunosuppressive Tumor Microenvironment. Cells 77 31330829
2023 IL4i1 and IDO1: Oxidases that control a tryptophan metabolic nexus in cancer. The Journal of biological chemistry 74 37196768
2006 The plasma membrane proteins Prm1 and Fig1 ascertain fidelity of membrane fusion during yeast mating. Molecular biology of the cell 71 17151357
2016 IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation. Brain : a journal of neurology 65 27797811
2020 Endogenous Indole Pyruvate Pathway for Tryptophan Metabolism Mediated by IL4I1. Journal of agricultural and food chemistry 62 32866000
2011 IL4I1: an inhibitor of the CD8⁺ antitumor T-cell response in vivo. European journal of immunology 62 21469114
2010 Dichotomy between factors inducing the immunosuppressive enzyme IL-4-induced gene 1 (IL4I1) in B lymphocytes and mononuclear phagocytes. European journal of immunology 58 20683900
2015 The immunosuppressive enzyme IL4I1 promotes FoxP3(+) regulatory T lymphocyte differentiation. European journal of immunology 52 25778793
1998 Primary structure of the snake venom L-amino acid oxidase shows high homology with the mouse B cell interleukin 4-induced Fig1 protein. Biochemical and biophysical research communications 48 9703950
2013 Antibacterial properties of the mammalian L-amino acid oxidase IL4I1. PloS one 45 23355881
2017 An Overview of l-Amino Acid Oxidase Functions from Bacteria to Mammals: Focus on the Immunoregulatory Phenylalanine Oxidase IL4I1. Molecules (Basel, Switzerland) 43 29206151
2002 Characterization of the human homolog of the IL-4 induced gene-1 (Fig1). Biochimica et biophysica acta 40 12031486
2015 Human spermatozoa possess an IL4I1 l-amino acid oxidase with a potential role in sperm function. Reproduction (Cambridge, England) 39 25767141
2012 Role of Fig1, a component of the low-affinity calcium uptake system, in growth and sexual development of filamentous fungi. Eukaryotic cell 35 22635922
2022 IL4I1 enhances PD-L1 expression through JAK/STAT signaling pathway in lung adenocarcinoma. Immunogenetics 33 36056935
2021 Single-cell analysis revealed that IL4I1 promoted ovarian cancer progression. Journal of translational medicine 32 34717685
2018 RRAD, IL4I1, CDKN1A, and SERPINE1 genes are potentially co-regulated by NF-κB and p53 transcription factors in cells exposed to high doses of ionizing radiation. BMC genomics 28 30419821
2015 Differential expression of the immunosuppressive enzyme IL4I1 in human induced Aiolos+, but not natural Helios+, FOXP3+ Treg cells. European journal of immunology 28 25446972
2021 Integrated analysis reveals the participation of IL4I1, ITGB7, and FUT7 in reshaping the TNBC immune microenvironment by targeting glycolysis. Annals of medicine 27 34134578
2021 IL4I1 Is Expressed by Head-Neck Cancer-Derived Mesenchymal Stromal Cells and Contributes to Suppress T Cell Proliferation. Journal of clinical medicine 24 34068423
2011 Fig1 facilitates calcium influx and localizes to membranes destined to undergo fusion during mating in Candida albicans. Eukaryotic cell 24 21216943
2016 IL4I1: Key immunoregulator at a crossroads of divergent T-cell functions. European journal of immunology 23 27726138
2024 IL4I1 in M2-like macrophage promotes glioma progression and is a promising target for immunotherapy. Frontiers in immunology 20 38250074
2021 What role for AHR activation in IL4I1-mediated immunosuppression ? Oncoimmunology 20 34026337
2019 Role of Low-Affinity Calcium System Member Fig1 Homologous Proteins in Conidiation and Trap-Formation of Nematode-trapping Fungus Arthrobotrys oligospora. Scientific reports 19 30872626
2013 FigA, a putative homolog of low-affinity calcium system member Fig1 in Saccharomyces cerevisiae, is involved in growth and asexual and sexual development in Aspergillus nidulans. Eukaryotic cell 19 24376003
2020 IL4I1 Accelerates the Expansion of Effector CD8+ T Cells at the Expense of Memory Precursors by Increasing the Threshold of T-Cell Activation. Frontiers in immunology 18 33343572
2023 IL4I1-catalyzed tryptophan metabolites mediate the anti-inflammatory function of cytokine-primed human muscle stem cells. Cell death discovery 16 37507432
2022 IL4I1 and tryptophan metabolites enhance AHR signals to facilitate colorectal cancer progression and immunosuppression. American journal of translational research 16 36505324
2024 Collagen extracellular matrix promotes gastric cancer immune evasion by activating IL4I1-AHR signaling. Translational oncology 15 39216468
2015 Alterations of the immunosuppressive IL4I1 enzyme activity induced by naturally occurring SNP/mutations. Genes and immunity 15 26673964
2023 Mechanical confinement promotes heat resistance of hepatocellular carcinoma via SP1/IL4I1/AHR axis. Cell reports. Medicine 14 37478857
2023 Human Chorionic Gonadotropin-Stimulated Interleukin-4-Induced-1 (IL4I1) Promotes Human Decidualization via Aryl Hydrocarbon Receptor. International journal of molecular sciences 13 36834576
2022 JMJD3 downregulates IL4i1 aggravating lipopolysaccharide-induced acute lung injury via H3K27 and H3K4 demethylation. Environmental toxicology 11 36537648
2020 Interleukin 4 inducible 1 gene (IL4I1) is induced in chicken phagocytes by Salmonella Enteritidis infection. Veterinary research 11 32404145
2024 Renal remodeling by CXCL10-CXCR3 axis-recruited mesenchymal stem cells and subsequent IL4I1 secretion in lupus nephritis. Signal transduction and targeted therapy 10 39557841
2023 Knockdown of IL4I1 Improved High Glucose-evoked Insulin Resistance in HepG2 Cells by Alleviating Inflammation and Lipotoxicity Through AHR Activation. Applied biochemistry and biotechnology 10 36913096
2022 IL4I1 binds to TMPRSS13 and competes with SARS-CoV-2 spike. Frontiers in immunology 9 36131918
2025 Tryptophan Metabolic Enzyme IL4I1 Inhibits Ferroptosis by Decreasing Ubiquitination of Nrf2 via I3P in Glioblastoma. Cell proliferation 7 40071723
2025 Knockout IL4I1 affects macrophages to improve poor efficacy of CD19 CAR-T combined with PD-1 inhibitor in relapsed/refractory diffuse large B-cell lymphoma. Journal of translational medicine 6 39844281
2023 Inhibitors of Interleukin 4 Induced Protein 1 (IL4I1) as Potential Treatment for Cancer. ACS medicinal chemistry letters 6 36793430
2018 An Antimicrobial Peptide Induces FIG1-Dependent Cell Death During Cell Cycle Arrest in Yeast. Frontiers in microbiology 5 29963019
2024 IL4I1: a novel molecular biomarker represents an inflamed tumor microenvironment and precisely predicts the molecular subtype and immunotherapy response of bladder cancer. Frontiers in pharmacology 4 38873416
2021 IL-4i1 Regulation of Immune Protection During Mycobacterium tuberculosis Infection. The Journal of infectious diseases 4 34739044
2025 Macrophage-mediated activation of the IL4I1/AhR axis is a key player in allergic rhinitis. International immunopharmacology 3 40080924
2025 PM2.5 Induced Nasal Mucosal Barrier Dysfunction and Epithelial-Mesenchymal Transition to Promote Chronic Rhinosinusitis Through IL4I1-AhR Signaling Pathway. Toxics 2 40559961
2025 IL4I1 attenuates myocardial infarction by inhibiting macrophage ferroptosis via the I3P/AHR/NRF2 signaling pathway. International immunopharmacology 2 40907328
2021 [The role of IL4I1 in immunoregulation: An update]. Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology 2 33441232
2025 Immunohistochemical Profiling of IDO1 and IL4I1 in Head and Neck Squamous Cell Carcinoma: Interplay for Metabolic Reprogramming? International journal of molecular sciences 1 40332319
2025 IL4I1 knockdown inhibits the epithelial-mesenchymal transition process in glioma via downregulation of the JAK2/STAT3 signaling pathway. Neoplasma 1 40353627
2025 Identification of potential IL4I1 inhibitors through structure-based virtual screening and molecular dynamics simulations. Journal of biomolecular structure & dynamics 1 40411435
2025 IL4I1 overexpression protects against nonalcoholic fatty liver disease in part by inhibiting the AKT/FOXO1 pathway-mediated Th17 cell differentiation. The Journal of biological chemistry 1 40769409
2025 IL4I1⁺ Macrophages and TDO2⁺ Myofibroblasts Drive AhR-Mediated Immunosuppression and Ferroptosis Resistance in Solid Predominant Lung Adenocarcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 1 41431173
2026 Conditional IL4I1 Inactivation Triggers Tumor-Associated Macrophage Reprogramming and CD8+ T-cell Reactivation to Control Melanoma Progression. Cancer immunology research 0 41537775
2026 Decoding IL4I1: The Core role of metabolism-driven immune regulation and new perspectives on disease targeting. Bioorganic chemistry 0 41616522
2026 Emerging roles of IL4I1 in regulating tumor immunity and ferroptosis. Biochimica et biophysica acta. Reviews on cancer 0 41690560
2026 l-amino acid oxidases Lao1 and Il4i1 are major determinants of early intestinal transcriptional responses to DSS-induced stress. Biochemical and biophysical research communications 0 42054897
2026 IL4I1+ macrophages drive hepatocellular carcinoma progression by responding to biomechanical cues. JHEP reports : innovation in hepatology 0 42096911
2026 IL4i1 activity generates oncometabolites that rescue neuroblastoma cells from oxidative death. Cell reports 0 42176266
2026 Metabolic checkpoint blockade of IL4I1 by ZY-MY-111 reactivates CD8+ T cell immunity and suppresses tumor growth. Acta pharmacologica Sinica 0 42252303
2025 Differential Effects of IL4I1 Protein on Lymphocytes From Healthy and Multiple Sclerosis Patients. Pharmacology research & perspectives 0 40102177
2025 Proteomic Identification of IL4I1 as a Therapeutic Target in P53-Mutant Endometrial Cancer. Cancers 0 41008831
2025 IDO1, IL4I1: Novel Immune Checkpoints in Breast Cancer Tumor-Associated Macrophages. Breast cancer (Dove Medical Press) 0 41458460

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