{"gene":"IL4I1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1997,"finding":"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.","method":"cDNA representational difference analysis (RDA subtraction), sequence analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cDNA isolation and sequence analysis with FAD-binding domain identification, single lab but foundational characterization","pmids":["9122225"],"is_preprint":false},{"year":1998,"finding":"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.","method":"cDNA sequencing, protein sequence similarity search","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — sequence homology analysis with structural implication, independently consistent with later biochemical confirmation","pmids":["9703950"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Genomic cloning, sequence analysis, structural homology mapping to LAAO crystal structure","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — structural inference from crystal structure homology with sequence conservation at active site, single lab","pmids":["12031486"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Stable HEK293 transfection, enzymatic activity assays, T-cell proliferation assays, blocking experiments, immunohistochemistry, flow cytometry","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro enzymatic characterization with multiple orthogonal functional assays (amino acid oxidase activity, H2O2 measurement, T-cell proliferation, enzymatic inhibition rescue), replicated across human and mouse proteins","pmids":["17356132"],"is_preprint":false},{"year":2010,"finding":"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.","method":"In vitro stimulation assays, transcription factor pathway inhibitors/activators, T-cell proliferation assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple stimuli tested with defined transcription factor pathway activation, single lab","pmids":["20683900"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Mouse tumor model, GP33 vaccination, flow cytometry for IFN-γ-producing CD8+ T cells, tumor incidence monitoring","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse tumor model with defined immune readout and dose-response (20% IL4I1-expressing cells sufficient for escape), multiple immunological parameters assessed","pmids":["21469114"],"is_preprint":false},{"year":2013,"finding":"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.","method":"In vitro bacterial growth assays, in vivo infection models, H2O2 measurement, catalase neutralization experiments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple bacterial strains tested with mechanistic dissection of H2O2 vs. amino acid depletion vs. ammonia, single lab","pmids":["23355881"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In vitro T-cell differentiation assays, phenylalanine deprivation experiments, H2O2 addition experiments, mTORC1 activity assays, IL4I1 from multiple sources tested","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple experimental conditions (Phe deprivation, H2O2 addition, mTORC1 readout) tested in both human and mouse cells, single lab","pmids":["25778793"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Exogenous expression system, enzymatic activity assays with different amino acid substrates, site-specific variants","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct enzymatic activity measurement with gain- and loss-of-function variants, single lab","pmids":["26673964"],"is_preprint":false},{"year":2015,"finding":"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).","method":"BMDM differentiation, siRNA knockdown, overexpression, gene expression profiling, T-cell activation assays, pharmacological inhibitors, STAT phosphorylation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (siRNA, OE, inhibitors, STAT readouts) in single lab","pmids":["26599209"],"is_preprint":false},{"year":2015,"finding":"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.","method":"LAAO enzymatic activity assays, immunolocalization, flow cytometry, tyrosine phosphorylation assays, catalase rescue experiments","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity confirmed, localization by immunostaining, functional effects blocked by catalase, single lab","pmids":["25767141"],"is_preprint":false},{"year":2016,"finding":"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.","method":"IL4I1 knockout mice, focal demyelination model, recombinant IL4I1 injection, splenocyte culture assays, EAE model with IL4I1 IV injection, histological analysis","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and recombinant protein rescue experiments with defined cellular/histological readouts across multiple mouse models","pmids":["27797811"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Pan-tissue AHR signature (NLP), metabolite profiling, mouse CLL model, cell motility assays, immune assays, IDO1 inhibitor experiments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — metabolite identification, AHR activation, in vivo mouse model, pan-cancer transcriptomic analysis, multiple orthogonal approaches","pmids":["32818467"],"is_preprint":false},{"year":2020,"finding":"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).","method":"IL4I1-overexpressing 293T cell line, metabolite measurement by mass spectrometry, CYP1A1 expression assays in dendritic cells","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression system with metabolite identification and AHR target gene readout, single lab","pmids":["32866000"],"is_preprint":false},{"year":2020,"finding":"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.","method":"IL4I1-deficient mouse model, acute LCMV infection, transgenic CD8 T-cell clone tracking, in vitro immune synapse stability assay, flow cytometry","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo with in vitro mechanistic follow-up (synapse stability), multiple immunological readouts","pmids":["33343572"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Recombinant mammalian-expressed IL4I1 vs. snake venom LAAO, cell viability assays, ferroptosis induction, I3P treatment, gene expression profiling, free radical scavenging assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — recombinant proteins compared, metabolite (I3P) identified and functionally validated, mechanistic dissection of scavenging vs. gene program, multiple orthogonal methods","pmids":["33646117"],"is_preprint":false},{"year":2018,"finding":"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.","method":"RNA-seq with TP53 and RELA silencing in irradiated U2-OS cells, ChIP-seq for p53 and RelA binding, qPCR validation","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and RNA-seq with gene silencing, two transcription factor binding and expression effects validated, single lab","pmids":["30419821"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Pulldown/binding assay, competition assay, TMPRSS13 overexpression, pseudotyped virus entry assay, flow cytometry for immune cell expression","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — binding interaction and competition demonstrated, multiple cell types characterized, single lab","pmids":["36131918"],"is_preprint":false},{"year":2022,"finding":"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.","method":"siRNA knockdown, Western blot for JAK/STAT pathway proteins and PD-L1, pharmacological rescue (RO8191), T cell cytotoxicity assay","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with pharmacological rescue validates pathway, single lab","pmids":["36056935"],"is_preprint":false},{"year":2022,"finding":"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.","method":"ChIP, siRNA/JMJD3 inhibitor (GSK-J4), in vivo ALI model, macrophage polarization assays, IL4I1 overexpression","journal":"Environmental toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validates histone methylation at IL4I1 locus, in vivo and in vitro rescue experiments, single lab","pmids":["36537648"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IL4I1-dependent mechanism in MuSCs with in vivo validation, AHR target gene identification, single lab","pmids":["37507432"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Cell culture with hCG stimulation, ornithine decarboxylase inhibition, IL4I1 metabolite treatment (I3P, I3A), AHR reporter assays, Epiregulin expression measurement, in vitro decidualization assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — causal pathway established with stimulus-metabolite-receptor-target gene chain, in vitro, single lab","pmids":["36834576"],"is_preprint":false},{"year":2023,"finding":"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.","method":"3D bioprinting-based thermal ablation system, SP1 manipulation, IL4I1 expression assays, tryptophan metabolite measurement, AHR inhibitor treatment, in vivo tumor recurrence model","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain SP1→IL4I1→tryptophan metabolites→AHR established with intervention at multiple steps, single lab","pmids":["37478857"],"is_preprint":false},{"year":2024,"finding":"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.","method":"IL4I1 genetic ablation in hUC-MSCs, in vivo LN mouse model, single-cell RNA sequencing, Th1 cell infiltration quantification","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic ablation with defined in vivo phenotype (Th1 suppression), single lab","pmids":["39557841"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO in vivo, metabolite (I3P) identified, mechanistic pathway validated with AHR inhibitor and NRF2 readouts, in vivo rescue experiment","pmids":["40907328"],"is_preprint":false},{"year":2025,"finding":"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.","method":"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","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — OE and KD with pathway activation readouts, pharmacological rescue validates AKT/FOXO1 involvement, in vivo and in vitro, single lab","pmids":["40769409"],"is_preprint":false},{"year":2025,"finding":"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.","method":"siRNA knockdown, Western blot, immunofluorescence for EMT markers and JAK2/STAT3, xenograft tumor model","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined pathway readout (JAK2/STAT3), in vivo validation, single lab","pmids":["40353627"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Transcriptomic analysis, I3P-Nrf2 binding assay, ubiquitination assay, Nrf2 knockdown, AHR inhibitor ML385, in vivo xenograft model","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct I3P-Nrf2 binding with ubiquitination mechanism, AHR-independent pathway established by inhibitor, in vivo validation, single lab","pmids":["40071723"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Macrophage-specific IL4I1 conditional knockout mice, murine melanoma models, chemical IL4I1 blockade, tumor growth and metastasis monitoring, T cell and macrophage functional assays","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with defined mechanistic readouts (antigen presentation, CD8 T-cell function), chemical blockade replication, in vivo","pmids":["41537775"],"is_preprint":false},{"year":2026,"finding":"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.","method":"Recombinant IL4i1 protein, metabolite treatment, ferroptosis induction, NRF2 pathway assays, AHR knockout/inhibitor controls, supernatant transfer experiments, IL4i1-KO autochthonous mouse NB model","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — recombinant protein, metabolite identification, AHR-independence demonstrated by KO controls, in vivo genetic model, multiple orthogonal methods","pmids":["42176266"],"is_preprint":false},{"year":2026,"finding":"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).","method":"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","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assay with mechanism (mixed inhibitor, competitive), in vivo efficacy, single lab","pmids":["42252303"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain (collagen→integrin αvβ1→IL4I1→KynA→AHR→T cell exhaustion) established with intervention at multiple steps, single lab","pmids":["39216468"],"is_preprint":false}],"current_model":"IL4I1 is a secreted FAD-dependent L-amino acid oxidase primarily expressed by myeloid antigen-presenting cells (macrophages, dendritic cells) and some B cells that catalyzes oxidative deamination of L-phenylalanine (primary substrate) and L-tryptophan, generating H2O2, ammonia, keto-acids, and indole metabolites (especially indole-3-pyruvate, I3P); it suppresses T-cell proliferation and effector function via H2O2-mediated TCRζ downregulation, mTORC1 inhibition, and reduced immune synapse stability; promotes FoxP3+ Treg differentiation partly through phenylalanine depletion; activates the aryl hydrocarbon receptor (AHR) via indole metabolites and kynurenic acid to drive immunosuppression; inhibits ferroptotic cell death through I3P-mediated free radical scavenging and NRF2 stabilization (AHR-independent); is regulated transcriptionally by NF-κB/STAT1 (myeloid cells), IL-4/STAT6 (B cells), SP1 (under mechanical stress), and epigenetically by JMJD3-mediated H3K4me3 demethylation; and binds surface receptor TMPRSS13 on immune cells, positioning IL4I1 as a metabolic immune checkpoint that promotes tumor immune escape, macrophage M2 polarization, and resistance to ferroptosis across diverse cancer types."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1997,"claim":"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","pmids":["9122225"],"confidence":"Medium","gaps":["Enzymatic activity not demonstrated","Substrate unknown","Cellular function undefined"]},{"year":2002,"claim":"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","pmids":["9703950","12031486"],"confidence":"Medium","gaps":["Predicted residues not yet mutationally validated","No direct enzymatic measurement"]},{"year":2007,"claim":"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","pmids":["17356132"],"confidence":"High","gaps":["TCRζ downregulation mechanism not fully resolved","In vivo relevance not yet shown"]},{"year":2010,"claim":"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","pmids":["20683900"],"confidence":"Medium","gaps":["Direct promoter occupancy not mapped here","Quantitative contribution of each pathway unresolved"]},{"year":2011,"claim":"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","pmids":["21469114"],"confidence":"High","gaps":["Metabolite mediators not yet identified","Mechanism of CD8 reduction not dissected"]},{"year":2013,"claim":"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","pmids":["23355881"],"confidence":"Medium","gaps":["Relative in vivo contributions context-dependent","Single lab"]},{"year":2015,"claim":"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","pmids":["25778793","26599209","26673964","25767141"],"confidence":"Medium","gaps":["Tryptophan metabolite identity not yet defined","Mechanism linking metabolism to STAT3/6 activation unclear"]},{"year":2016,"claim":"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","pmids":["27797811"],"confidence":"High","gaps":["Metabolite mediator not identified","Direct vs. indirect macrophage effects unresolved"]},{"year":2018,"claim":"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","pmids":["30419821"],"confidence":"Medium","gaps":["Functional consequence of radiation-induced IL4I1 not tested","Single cell line"]},{"year":2020,"claim":"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","pmids":["32818467","32866000"],"confidence":"High","gaps":["Receptor/uptake of metabolites by AHR-expressing cells not fully mapped","Relative weighting of H2O2 vs. indole signaling unresolved"]},{"year":2020,"claim":"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","pmids":["33343572"],"confidence":"High","gaps":["Molecular basis of synapse destabilization unresolved","Reconciliation with suppressive role context-specific"]},{"year":2021,"claim":"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","pmids":["33646117"],"confidence":"High","gaps":["AHR-dependence of antioxidant program not yet separated","Direct molecular target of I3P not defined here"]},{"year":2022,"claim":"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","pmids":["36131918","36056935","36537648"],"confidence":"Medium","gaps":["Functional consequence of TMPRSS13 binding for signaling unclear","Reciprocal validation of the interaction limited"]},{"year":2023,"claim":"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","pmids":["37507432","36834576","37478857"],"confidence":"Medium","gaps":["Generality across tissues untested","Each pathway from single lab"]},{"year":2024,"claim":"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","pmids":["39557841","39216468"],"confidence":"Medium","gaps":["Direct metabolite measurement in MSC setting limited","Relative contribution of KynA vs. I3P to T-cell suppression unclear"]},{"year":2025,"claim":"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","pmids":["40071723","40907328","40769409","40353627"],"confidence":"High","gaps":["Structural basis of I3P-NRF2 binding not solved","Crosstalk between AHR-dependent and -independent NRF2 routes unresolved"]},{"year":2026,"claim":"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","pmids":["41537775","42176266","42252303"],"confidence":"High","gaps":["Clinical translation untested","Selectivity and pharmacodynamics of inhibitors require further definition"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,8,15,1,2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,8]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[12,13,15]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,11,23]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,5,7,14,28]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,8,12,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[15,24,27,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,27,25]}],"complexes":[],"partners":["TMPRSS13"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96RQ9","full_name":"L-amino-acid oxidase","aliases":["Interleukin-4-induced protein 1","IL4-induced protein 1","hIL4I1","Protein Fig-1","hFIG1"],"length_aa":567,"mass_kda":62.9,"function":"Secreted L-amino-acid oxidase that acts as a key immunoregulator (PubMed:17356132, PubMed:32818467, PubMed:32866000). Has preference for L-aromatic amino acids: converts phenylalanine (Phe), tyrosine (Tyr) and tryptophan (Trp) to phenylpyruvic acid (PP), hydroxyphenylpyruvic acid (HPP), and indole-3-pyruvic acid (I3P), respectively (PubMed:17356132, PubMed:32818467, PubMed:32866000). Also has weak L-arginine oxidase activity (PubMed:26673964). Acts as a negative regulator of anti-tumor immunity by mediating Trp degradation via an indole pyruvate pathway that activates the transcription factor AHR (PubMed:32818467, PubMed:32866000). IL4I1-mediated Trp catabolism generates I3P, giving rise to indole metabolites (indole-3-acetic acid (IAA) and indole-3-aldehyde (I3A)) and kynurenic acid, which act as ligands for AHR, a ligand-activated transcription factor that plays important roles in immunity and cancer (PubMed:32818467, PubMed:32866000). AHR activation by indoles following IL4I1-mediated Trp degradation enhances tumor progression by promoting cancer cell motility and suppressing adaptive immunity (PubMed:32818467). Also has an immunoregulatory function in some immune cells, probably by mediating Trp degradation and promoting downstream AHR activation: inhibits T-cell activation and proliferation, promotes the differentiation of naive CD4(+) T-cells into FOXP3(+) regulatory T-cells (Treg) and regulates the development and function of B-cells (PubMed:17356132, PubMed:25446972, PubMed:25778793, PubMed:28891065). Also regulates M2 macrophage polarization by inhibiting T-cell activation (By similarity). Also has antibacterial properties by inhibiting growth of Gram negative and Gram positive bacteria through the production of NH4(+) and H2O2 (PubMed:23355881)","subcellular_location":"Secreted; Lysosome; Cytoplasmic vesicle, secretory vesicle, acrosome","url":"https://www.uniprot.org/uniprotkb/Q96RQ9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL4I1","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL4I1","total_profiled":1310},"omim":[{"mim_id":"609742","title":"INTERLEUKIN 4-INDUCED GENE 1; IL4I1","url":"https://www.omim.org/entry/609742"},{"mim_id":"605815","title":"NUCLEOPORIN, 62-KD; NUP62","url":"https://www.omim.org/entry/605815"},{"mim_id":"603149","title":"INTERLEUKIN 17A; IL17A","url":"https://www.omim.org/entry/603149"},{"mim_id":"602943","title":"RAR-RELATED ORPHAN RECEPTOR C; RORC","url":"https://www.omim.org/entry/602943"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Acrosome","reliability":"Supported"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":17.1},{"tissue":"testis","ntpm":27.5}],"url":"https://www.proteinatlas.org/search/IL4I1"},"hgnc":{"alias_symbol":["FIG1"],"prev_symbol":[]},"alphafold":{"accession":"Q96RQ9","domains":[{"cath_id":"3.50.50.60","chopping":"33-90_265-350_471-507","consensus_level":"high","plddt":94.8817,"start":33,"end":507},{"cath_id":"1.10.405.10","chopping":"157-257","consensus_level":"medium","plddt":96.2153,"start":157,"end":257}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RQ9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RQ9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96RQ9-F1-predicted_aligned_error_v6.png","plddt_mean":86.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL4I1","jax_strain_url":"https://www.jax.org/strain/search?query=IL4I1"},"sequence":{"accession":"Q96RQ9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96RQ9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96RQ9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96RQ9"}},"corpus_meta":[{"pmid":"32818467","id":"PMC_32818467","title":"IL4I1 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The Fig1 cDNA encodes a predicted 70-kDa flavoprotein with homology to monoamine oxidases, particularly in FAD-binding domains, suggesting it is a flavoenzyme.\",\n      \"method\": \"cDNA representational difference analysis (RDA subtraction), sequence analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cDNA isolation and sequence analysis with FAD-binding domain identification, single lab but foundational characterization\",\n      \"pmids\": [\"9122225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"cDNA sequencing, protein sequence similarity search\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — sequence homology analysis with structural implication, independently consistent with later biochemical confirmation\",\n      \"pmids\": [\"9703950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Genomic cloning, sequence analysis, structural homology mapping to LAAO crystal structure\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — structural inference from crystal structure homology with sequence conservation at active site, single lab\",\n      \"pmids\": [\"12031486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Stable HEK293 transfection, enzymatic activity assays, T-cell proliferation assays, blocking experiments, immunohistochemistry, flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro enzymatic characterization with multiple orthogonal functional assays (amino acid oxidase activity, H2O2 measurement, T-cell proliferation, enzymatic inhibition rescue), replicated across human and mouse proteins\",\n      \"pmids\": [\"17356132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro stimulation assays, transcription factor pathway inhibitors/activators, T-cell proliferation assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple stimuli tested with defined transcription factor pathway activation, single lab\",\n      \"pmids\": [\"20683900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse tumor model, GP33 vaccination, flow cytometry for IFN-γ-producing CD8+ T cells, tumor incidence monitoring\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo mouse tumor model with defined immune readout and dose-response (20% IL4I1-expressing cells sufficient for escape), multiple immunological parameters assessed\",\n      \"pmids\": [\"21469114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro bacterial growth assays, in vivo infection models, H2O2 measurement, catalase neutralization experiments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple bacterial strains tested with mechanistic dissection of H2O2 vs. amino acid depletion vs. ammonia, single lab\",\n      \"pmids\": [\"23355881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro T-cell differentiation assays, phenylalanine deprivation experiments, H2O2 addition experiments, mTORC1 activity assays, IL4I1 from multiple sources tested\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple experimental conditions (Phe deprivation, H2O2 addition, mTORC1 readout) tested in both human and mouse cells, single lab\",\n      \"pmids\": [\"25778793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Exogenous expression system, enzymatic activity assays with different amino acid substrates, site-specific variants\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct enzymatic activity measurement with gain- and loss-of-function variants, single lab\",\n      \"pmids\": [\"26673964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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).\",\n      \"method\": \"BMDM differentiation, siRNA knockdown, overexpression, gene expression profiling, T-cell activation assays, pharmacological inhibitors, STAT phosphorylation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (siRNA, OE, inhibitors, STAT readouts) in single lab\",\n      \"pmids\": [\"26599209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"LAAO enzymatic activity assays, immunolocalization, flow cytometry, tyrosine phosphorylation assays, catalase rescue experiments\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity confirmed, localization by immunostaining, functional effects blocked by catalase, single lab\",\n      \"pmids\": [\"25767141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"IL4I1 knockout mice, focal demyelination model, recombinant IL4I1 injection, splenocyte culture assays, EAE model with IL4I1 IV injection, histological analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and recombinant protein rescue experiments with defined cellular/histological readouts across multiple mouse models\",\n      \"pmids\": [\"27797811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Pan-tissue AHR signature (NLP), metabolite profiling, mouse CLL model, cell motility assays, immune assays, IDO1 inhibitor experiments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — metabolite identification, AHR activation, in vivo mouse model, pan-cancer transcriptomic analysis, multiple orthogonal approaches\",\n      \"pmids\": [\"32818467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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).\",\n      \"method\": \"IL4I1-overexpressing 293T cell line, metabolite measurement by mass spectrometry, CYP1A1 expression assays in dendritic cells\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression system with metabolite identification and AHR target gene readout, single lab\",\n      \"pmids\": [\"32866000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"IL4I1-deficient mouse model, acute LCMV infection, transgenic CD8 T-cell clone tracking, in vitro immune synapse stability assay, flow cytometry\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo with in vitro mechanistic follow-up (synapse stability), multiple immunological readouts\",\n      \"pmids\": [\"33343572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant mammalian-expressed IL4I1 vs. snake venom LAAO, cell viability assays, ferroptosis induction, I3P treatment, gene expression profiling, free radical scavenging assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — recombinant proteins compared, metabolite (I3P) identified and functionally validated, mechanistic dissection of scavenging vs. gene program, multiple orthogonal methods\",\n      \"pmids\": [\"33646117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"RNA-seq with TP53 and RELA silencing in irradiated U2-OS cells, ChIP-seq for p53 and RelA binding, qPCR validation\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and RNA-seq with gene silencing, two transcription factor binding and expression effects validated, single lab\",\n      \"pmids\": [\"30419821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Pulldown/binding assay, competition assay, TMPRSS13 overexpression, pseudotyped virus entry assay, flow cytometry for immune cell expression\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — binding interaction and competition demonstrated, multiple cell types characterized, single lab\",\n      \"pmids\": [\"36131918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, Western blot for JAK/STAT pathway proteins and PD-L1, pharmacological rescue (RO8191), T cell cytotoxicity assay\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with pharmacological rescue validates pathway, single lab\",\n      \"pmids\": [\"36056935\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, siRNA/JMJD3 inhibitor (GSK-J4), in vivo ALI model, macrophage polarization assays, IL4I1 overexpression\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validates histone methylation at IL4I1 locus, in vivo and in vitro rescue experiments, single lab\",\n      \"pmids\": [\"36537648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IL4I1-dependent mechanism in MuSCs with in vivo validation, AHR target gene identification, single lab\",\n      \"pmids\": [\"37507432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Cell culture with hCG stimulation, ornithine decarboxylase inhibition, IL4I1 metabolite treatment (I3P, I3A), AHR reporter assays, Epiregulin expression measurement, in vitro decidualization assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — causal pathway established with stimulus-metabolite-receptor-target gene chain, in vitro, single lab\",\n      \"pmids\": [\"36834576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"3D bioprinting-based thermal ablation system, SP1 manipulation, IL4I1 expression assays, tryptophan metabolite measurement, AHR inhibitor treatment, in vivo tumor recurrence model\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain SP1→IL4I1→tryptophan metabolites→AHR established with intervention at multiple steps, single lab\",\n      \"pmids\": [\"37478857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"IL4I1 genetic ablation in hUC-MSCs, in vivo LN mouse model, single-cell RNA sequencing, Th1 cell infiltration quantification\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic ablation with defined in vivo phenotype (Th1 suppression), single lab\",\n      \"pmids\": [\"39557841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO in vivo, metabolite (I3P) identified, mechanistic pathway validated with AHR inhibitor and NRF2 readouts, in vivo rescue experiment\",\n      \"pmids\": [\"40907328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — OE and KD with pathway activation readouts, pharmacological rescue validates AKT/FOXO1 involvement, in vivo and in vitro, single lab\",\n      \"pmids\": [\"40769409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown, Western blot, immunofluorescence for EMT markers and JAK2/STAT3, xenograft tumor model\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined pathway readout (JAK2/STAT3), in vivo validation, single lab\",\n      \"pmids\": [\"40353627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Transcriptomic analysis, I3P-Nrf2 binding assay, ubiquitination assay, Nrf2 knockdown, AHR inhibitor ML385, in vivo xenograft model\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct I3P-Nrf2 binding with ubiquitination mechanism, AHR-independent pathway established by inhibitor, in vivo validation, single lab\",\n      \"pmids\": [\"40071723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Macrophage-specific IL4I1 conditional knockout mice, murine melanoma models, chemical IL4I1 blockade, tumor growth and metastasis monitoring, T cell and macrophage functional assays\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with defined mechanistic readouts (antigen presentation, CD8 T-cell function), chemical blockade replication, in vivo\",\n      \"pmids\": [\"41537775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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.\",\n      \"method\": \"Recombinant IL4i1 protein, metabolite treatment, ferroptosis induction, NRF2 pathway assays, AHR knockout/inhibitor controls, supernatant transfer experiments, IL4i1-KO autochthonous mouse NB model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — recombinant protein, metabolite identification, AHR-independence demonstrated by KO controls, in vivo genetic model, multiple orthogonal methods\",\n      \"pmids\": [\"42176266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"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).\",\n      \"method\": \"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\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assay with mechanism (mixed inhibitor, competitive), in vivo efficacy, single lab\",\n      \"pmids\": [\"42252303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain (collagen→integrin αvβ1→IL4I1→KynA→AHR→T cell exhaustion) established with intervention at multiple steps, single lab\",\n      \"pmids\": [\"39216468\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL4I1 is a secreted FAD-dependent L-amino acid oxidase primarily expressed by myeloid antigen-presenting cells (macrophages, dendritic cells) and some B cells that catalyzes oxidative deamination of L-phenylalanine (primary substrate) and L-tryptophan, generating H2O2, ammonia, keto-acids, and indole metabolites (especially indole-3-pyruvate, I3P); it suppresses T-cell proliferation and effector function via H2O2-mediated TCRζ downregulation, mTORC1 inhibition, and reduced immune synapse stability; promotes FoxP3+ Treg differentiation partly through phenylalanine depletion; activates the aryl hydrocarbon receptor (AHR) via indole metabolites and kynurenic acid to drive immunosuppression; inhibits ferroptotic cell death through I3P-mediated free radical scavenging and NRF2 stabilization (AHR-independent); is regulated transcriptionally by NF-κB/STAT1 (myeloid cells), IL-4/STAT6 (B cells), SP1 (under mechanical stress), and epigenetically by JMJD3-mediated H3K4me3 demethylation; and binds surface receptor TMPRSS13 on immune cells, positioning IL4I1 as a metabolic immune checkpoint that promotes tumor immune escape, macrophage M2 polarization, and resistance to ferroptosis across diverse cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#3, #12]. First identified as the immediate-early IL-4-inducible B-cell gene Fig1 encoding a flavoprotein with monoamine oxidase/L-amino acid oxidase homology [#0, #1, #2], 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 [#3, #8]. 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 [#3, #7, #14]. 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 [#12, #13, #20]. 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 [#15, #24, #27, #29]. 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 [#5, #9, #28, #30]. 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 [#4, #16, #19, #22]. IL4I1 also binds the immune-cell surface protein TMPRSS13 [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established IL4I1 as an IL-4-inducible B-cell gene whose sequence predicted a flavoenzyme, framing the question of its catalytic identity.\",\n      \"evidence\": \"cDNA representational difference analysis and sequence/FAD-domain analysis in B cells\",\n      \"pmids\": [\"9122225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic activity not demonstrated\", \"Substrate unknown\", \"Cellular function undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Genomic cloning and homology mapping of human and mouse orthologs\",\n      \"pmids\": [\"9703950\", \"12031486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Predicted residues not yet mutationally validated\", \"No direct enzymatic measurement\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Stable HEK293 expression, enzymatic and H2O2 assays, T-cell proliferation with enzymatic blockade\",\n      \"pmids\": [\"17356132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TCRζ downregulation mechanism not fully resolved\", \"In vivo relevance not yet shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro stimulation with pathway inhibitors/activators and T-cell proliferation readouts\",\n      \"pmids\": [\"20683900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct promoter occupancy not mapped here\", \"Quantitative contribution of each pathway unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed in vivo that IL4I1 suppresses the CD8+ antitumor response, moving the enzyme from in vitro suppressor to a driver of tumor immune escape.\",\n      \"evidence\": \"Mouse melanoma model co-expressing IL4I1 and GP33 with vaccination and IFN-γ+ CD8 readouts\",\n      \"pmids\": [\"21469114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Metabolite mediators not yet identified\", \"Mechanism of CD8 reduction not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended IL4I1 function to antibacterial defense, showing H2O2, ammonia-driven basification, and phenylalanine depletion as effector mechanisms.\",\n      \"evidence\": \"In vitro and in vivo bacterial growth assays with catalase neutralization\",\n      \"pmids\": [\"23355881\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative in vivo contributions context-dependent\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"T-cell differentiation, Phe-deprivation, mTORC1 assays, BMDM polarization, enzymatic variant assays, sperm LAAO localization\",\n      \"pmids\": [\"25778793\", \"26599209\", \"26673964\", \"25767141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tryptophan metabolite identity not yet defined\", \"Mechanism linking metabolism to STAT3/6 activation unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic KO and recombinant rescue established a tissue-protective role in CNS, with IL4I1 limiting proinflammatory macrophages and supporting remyelination.\",\n      \"evidence\": \"IL4I1-knockout mice, focal demyelination, recombinant protein rescue, EAE model\",\n      \"pmids\": [\"27797811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Metabolite mediator not identified\", \"Direct vs. indirect macrophage effects unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified antagonistic NF-κB/p53 co-regulation of IL4I1 under ionizing radiation, adding a stress-responsive layer to its transcriptional control.\",\n      \"evidence\": \"RNA-seq with TP53/RELA silencing and ChIP-seq in irradiated U2-OS cells\",\n      \"pmids\": [\"30419821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of radiation-induced IL4I1 not tested\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pan-tumor AHR signature, metabolite profiling, mouse CLL model, IDO1 inhibitor experiments, DC CYP1A1 readouts\",\n      \"pmids\": [\"32818467\", \"32866000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/uptake of metabolites by AHR-expressing cells not fully mapped\", \"Relative weighting of H2O2 vs. indole signaling unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"IL4I1-deficient mice, acute LCMV infection, TCR clone tracking, in vitro synapse stability assay\",\n      \"pmids\": [\"33343572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of synapse destabilization unresolved\", \"Reconciliation with suppressive role context-specific\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Recombinant IL4I1 vs. venom LAAO, ferroptosis assays, I3P treatment, gene profiling\",\n      \"pmids\": [\"33646117\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"AHR-dependence of antioxidant program not yet separated\", \"Direct molecular target of I3P not defined here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added regulatory and interaction detail: TMPRSS13 surface binding, JAK/STAT-mediated PD-L1 upregulation, and JMJD3/histone-demethylation control of IL4I1 transcription.\",\n      \"evidence\": \"Pulldown/competition assays, siRNA with JAK/STAT rescue, ChIP and inhibitor experiments in macrophage/lung models\",\n      \"pmids\": [\"36131918\", \"36056935\", \"36537648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of TMPRSS13 binding for signaling unclear\", \"Reciprocal validation of the interaction limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"MuSC priming, hCG/endometrial decidualization assays, 3D bioprinting thermal ablation with SP1 manipulation and AHR inhibition\",\n      \"pmids\": [\"37507432\", \"36834576\", \"37478857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality across tissues untested\", \"Each pathway from single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"IL4I1 genetic ablation in hUC-MSCs in LN model; 3D collagen integrin αvβ1–IL4I1–KynA–AHR chain with CAR-T co-culture\",\n      \"pmids\": [\"39557841\", \"39216468\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct metabolite measurement in MSC setting limited\", \"Relative contribution of KynA vs. I3P to T-cell suppression unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"I3P-NRF2 binding/ubiquitination assays with AHR inhibitor controls, NRF2 KD, macrophage MI model, AKT/FOXO1 and JAK2/STAT3 pathway manipulation, xenografts\",\n      \"pmids\": [\"40071723\", \"40907328\", \"40769409\", \"40353627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of I3P-NRF2 binding not solved\", \"Crosstalk between AHR-dependent and -independent NRF2 routes unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"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.\",\n      \"evidence\": \"Macrophage-specific conditional KO in melanoma, IL4i1-KO neuroblastoma model, ZY-MY-111 enzymatic inhibition and syngeneic tumor efficacy\",\n      \"pmids\": [\"41537775\", \"42176266\", \"42252303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical translation untested\", \"Selectivity and pharmacodynamics of inhibitors require further definition\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 8, 15, 1, 2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 8]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [12, 13, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 11, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 5, 7, 14, 28]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 8, 12, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15, 24, 27, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 27, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TMPRSS13\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}