{"gene":"LOXL4","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"LOXL4 was identified as a novel lysyl oxidase family member with a conserved C-terminal copper-binding site, lysyl and tyrosyl residues, and a cytokine receptor-like domain. It contains four N-terminal SRCR domains, one of which has a unique 13 amino acid insertion encoded by a short exon not present in LOXL2 or LOXL3. The gene is located on chromosome 10q24 and spans 14 exons.","method":"cDNA cloning, sequence analysis, genomic structure determination","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct molecular characterization of gene/protein structure, foundational identification paper","pmids":["11691588"],"is_preprint":false},{"year":2007,"finding":"Reintroduction of LOXL4 into human bladder cancer cells decreased colony formation ability and antagonized Ras in activating the ERK signaling pathway, establishing LOXL4 as a functional tumor suppressor acting through inhibition of the Ras/ERK pathway.","method":"Gene reintroduction (overexpression), colony formation assay, ERK signaling western blot, promoter methylation analysis","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment with defined pathway readout (Ras/ERK), single lab, two orthogonal methods","pmids":["17456585"],"is_preprint":false},{"year":2008,"finding":"LOXL4 gene overexpression in HNSCC cells is driven by de novo transcription, with TATA (-25) and SP1 (-181) binding sites showing increased nuclear extract binding activity in HNSCC cells compared to normal epithelial cells, indicating these transcription factors regulate LOXL4 upregulation.","method":"Promoter deletion analysis, reporter gene assays, DNA-binding (EMSA) experiments with nuclear extracts","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter analysis with DNA-binding experiments, single lab, multiple constructs tested","pmids":["18949373"],"is_preprint":false},{"year":2008,"finding":"LOXL4 protein in cultured primary hypopharyngeal HTB-43 carcinoma cells localizes perinuclearly and at the cell surface, but not in the nucleus, suggesting cell surface-associated functions in tumor cell adhesion and extracellular matrix interactions.","method":"Immunocytochemistry in cultured HNSCC cells with LOXL4-specific antibody","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct subcellular localization by immunocytochemistry, replicated across HNSCC studies, single method","pmids":["18499440"],"is_preprint":false},{"year":2013,"finding":"TGF-β1 induces LOXL4 expression in aortic endothelial cells via a mechanism requiring both a distal AP-1 site and a Smad binding element in the LOXL4 promoter. Functional cooperation between Smad proteins and the AP-1 complex composed of JunB/Fra2 mediates TGF-β1 induction, involving ERK-dependent phosphorylation of Fra2. LOXL4 is extracellularly secreted and contributes to ECM deposition and assembly.","method":"Promoter deletion mapping, mutagenesis analysis, reporter gene assays, western blotting for ERK phosphorylation, chromatin immunoprecipitation, secretion assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter mutagenesis with functional validation, multiple orthogonal methods (ChIP, reporter assay, mutagenesis), single rigorous study","pmids":["23572561"],"is_preprint":false},{"year":2014,"finding":"LOXL4 promotes gastric cancer cell proliferation, migration and invasion, and activates the FAK/Src pathway to enhance cell-extracellular matrix adhesion. Recombinant human LOXL4 protein also promoted GC cell proliferation and migration, indicating extracellular LOXL4 activity.","method":"Overexpression, RNA interference, recombinant protein treatment, western blot for FAK/Src pathway, migration/invasion assays","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional gain/loss-of-function with defined pathway readout, recombinant protein validation, single lab","pmids":["25216702"],"is_preprint":false},{"year":2014,"finding":"LOXL4 is a direct target of miR-193a-3p; miR-193a-3p promotes multi-drug resistance in bladder cancer cells through suppression of LOXL4, and this resistance is mediated downstream via the Oxidative Stress pathway.","method":"miRNA overexpression/inhibition, luciferase reporter assay, xenograft tumor model, oxidative stress pathway analysis","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase assay plus in vivo xenograft, single lab, two orthogonal methods","pmids":["25311867"],"is_preprint":false},{"year":2017,"finding":"LOXL4 knockdown in triple-negative breast cancer cells increased primary tumor growth and lung colonization in mouse xenograft models, accompanied by increased collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging showed LOXL4 knockdown resulted in thickening of collagen bundles, indicating LOXL4 suppresses collagen synthesis, deposition, and structural changes in the ECM.","method":"shRNA knockdown, mouse xenograft model, second harmonic generation imaging, western blotting for collagen-related proteins","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional KD with defined ECM phenotype, multiple orthogonal methods (SHG imaging, western blot), single lab","pmids":["28060764"],"is_preprint":false},{"year":2019,"finding":"HCC-derived exosomes transfer LOXL4 between HCC cells and to HUVECs. Intracellular (but not extracellular) LOXL4 promotes cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. Exosome-transferred LOXL4 promotes angiogenesis via a paracrine mechanism.","method":"Exosome isolation and characterization, overexpression/shRNA knockdown, deletion mutants including amine oxidase domain mutants, western blot for FAK/Src, migration assays, in vivo metastasis models","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (domain deletion mutants, exosome transfer, in vivo models, pathway western blot), single lab with rigorous controls","pmids":["30704479"],"is_preprint":false},{"year":2019,"finding":"5-azacytidine (5-aza-CR) induces LOXL4 upregulation in liver cancer cells, and LOXL4 subsequently binds the basic domain of p53 via its low-isoelectric point region, inducing reactivation of compromised wild-type p53 and resulting in cell death. The LOXL4-p53 interaction was identified through genome-wide screening.","method":"Genome-wide screen, co-immunoprecipitation (LOXL4-p53 binding), domain mapping, xenograft tumor model, cell viability assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — protein-protein interaction (Co-IP with domain mapping), functional in vitro and in vivo validation, single lab with multiple orthogonal methods","pmids":["30728460"],"is_preprint":false},{"year":2020,"finding":"EZH2 inhibition enhances miR-30d and miR-29b transcription via promoter binding, reducing LOXL4 expression. LOXL4 was identified as a direct target of miR-29b and miR-30d (validated by dual-luciferase reporter assay and ChIP). EZH2-mediated epigenetic silencing of miR-29b/miR-30d results in elevated LOXL4, promoting breast cancer cell proliferation, migration, and metastasis.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation, qRT-PCR, western blotting, xenograft experiments","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct target validation by luciferase+ChIP, in vivo validation, single lab with multiple orthogonal methods","pmids":["32754259"],"is_preprint":false},{"year":2021,"finding":"Genetic ablation of LOXL4 in mice did not induce more severe thoracic or abdominal aortic aneurysm compared to wild-type mice under angiotensin II infusion, indicating LOXL4 does not play a major role in angiotensin II-induced aortic aneurysm development.","method":"LOXL4 knockout mouse generation, angiotensin II subcutaneous infusion, aortic aneurysm assessment","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean knockout mouse model with defined phenotypic readout (negative result), single lab, single study","pmids":["33807332"],"is_preprint":false},{"year":2023,"finding":"Genetic ablation of LOXL4 (but not LOXL2) markedly disrupts pathological collagen cross-linking and fibrosis in the lung. Combined knockout of Loxl2 and Loxl4 does not offer additive antifibrotic effects over Loxl4 deletion alone, and LOXL4 deficiency decreases expression of other LOX family members including Loxl2, establishing LOXL4 as the primary LOX activity underlying pathological collagen cross-linking in lung fibrosis.","method":"Genetic knockout mice (Loxl2 KO, Loxl4 KO, double KO), pulmonary fibrosis model, collagen cross-linking analysis, gene expression analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockouts with quantitative collagen cross-linking readout, comparison of single vs double KO, rigorous epistasis analysis","pmids":["37235663"],"is_preprint":false},{"year":2023,"finding":"LOXL4 shuttled by tumor cell-derived extracellular vesicles is delivered into macrophages, where it activates STAT1 signaling to induce PD-L1 expression, suppressing CD8+ T cell killing activity and promoting immune escape in hepatocellular carcinoma.","method":"EV isolation and delivery, in vitro macrophage/CD8+ T cell co-culture assay, in vivo orthotopic xenograft model, western blot for STAT1/PD-L1","journal":"Journal of immunotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mechanism (EV delivery → STAT1/PD-L1 axis) validated in vitro and in vivo, single lab, multiple methods","pmids":["38047403"],"is_preprint":false},{"year":2023,"finding":"ZEB1 (in its Zn2+-bound active form) acts as a transcription factor that drives expression of LOXL1 and LOXL4. Mutation of the Zn-finger motifs of ZEB1 (MutZEB1 ΔZn) leads to significant downregulation of LOXL1 and LOXL4, loss of EMT, and stalled invasion in MDA-MB-231 cells.","method":"Stable expression of MutZEB1 (ΔZn) in MDA-MB-231 cells, invasion assays, RNA-Seq analysis","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional genetic approach with defined invasion phenotype and transcriptomic validation, single lab","pmids":["36910659"],"is_preprint":false},{"year":2025,"finding":"TGF-β1 decreases LOXL4 protein (but not mRNA) expression in MDA-MB-231 breast cancer cells via proteasomal degradation through MEK/ERK pathway activation. Bortezomib (proteasomal inhibitor) suppresses TGF-β1-mediated LOXL4 reduction and inhibits TGF-β1-induced MEK/ERK pathways. N-glycosylation dysregulation is involved in reduction of LOXL4 secretion.","method":"Proteasomal inhibitor treatment, MEK/ERK inhibition, ROS measurement, western blotting for LOXL4 protein vs. mRNA levels, N-glycosylation analysis","journal":"Journal of receptor and signal transduction research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic dissection of post-translational regulation using pharmacological inhibitors and mRNA vs. protein comparison, single lab","pmids":["39862152"],"is_preprint":false},{"year":2026,"finding":"LOXL4 promotes ubiquitination and degradation of SOCS3 (suppressor of cytokine signaling 3), relieving SOCS3-mediated inhibition of JAK2 and leading to sustained STAT3 activation. This LOXL4-SOCS3-STAT3 axis enhances DNA damage repair, inhibits apoptosis, and fosters an immunosuppressive tumor microenvironment, driving radiotherapy resistance in glioma.","method":"Co-immunoprecipitation, mass spectrometry, stable RT-resistant cell models, functional assays for DNA repair and apoptosis, orthotopic glioma mouse model","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and mass spectrometry identify SOCS3 as binding partner/substrate, in vivo validation, single lab","pmids":["42134289"],"is_preprint":false}],"current_model":"LOXL4 is a secreted, copper-dependent amine oxidase that catalyzes collagen and elastin cross-linking to regulate extracellular matrix homeostasis, and is the primary LOX family member responsible for pathological collagen cross-linking in lung fibrosis; intracellularly, LOXL4 promotes cell migration and invasion via its amine oxidase activity through hydrogen peroxide-mediated activation of the FAK/Src pathway, can bind and reactivate wild-type p53 to suppress liver cancer, and can promote ubiquitination and degradation of SOCS3 to activate JAK2/STAT3 signaling; its expression is transcriptionally induced by TGF-β1 through cooperative Smad/JunB-Fra2 (AP-1) signaling and by the Zn2+-activated transcription factor ZEB1, while being subject to proteasomal degradation downstream of TGF-β1/MEK/ERK, and is regulated by multiple microRNAs (miR-193a-3p, miR-135a-5p, miR-183-5p, miR-328-5p, miR-29b, miR-30d); LOXL4 can also be packaged into exosomes/extracellular vesicles and transferred to recipient cells (including macrophages and endothelial cells) to promote angiogenesis and immune escape via STAT1/PD-L1 activation, and acts as a tumor suppressor in bladder cancer by inhibiting the Ras/ERK pathway."},"narrative":{"mechanistic_narrative":"LOXL4 is a secreted, copper-dependent lysyl oxidase family member that catalyzes extracellular matrix collagen cross-linking and, beyond this canonical role, exerts context-dependent control over tumor cell signaling, immune evasion, and angiogenesis [PMID:11691588, PMID:37235663]. Structurally it is defined by a conserved C-terminal copper-binding catalytic domain plus four N-terminal SRCR domains, including one bearing a unique 13-amino-acid insertion that distinguishes it from LOXL2 and LOXL3 [PMID:11691588]. In the lung, genetic ablation studies establish LOXL4 as the dominant LOX family activity driving pathological collagen cross-linking in fibrosis, with LOXL4 loss reducing fibrosis more strongly than LOXL2 loss and even lowering expression of other LOX members [PMID:37235663]. Its expression is transcriptionally induced by TGF-β1 through cooperative Smad and JunB/Fra2 (AP-1) signaling at the LOXL4 promoter and by the Zn2+-activated transcription factor ZEB1, which couples LOXL4 to EMT and invasion [PMID:23572561, PMID:36910659], while at the protein level TGF-β1 can conversely drive its proteasomal degradation through MEK/ERK [PMID:39862152], and multiple microRNAs (including miR-193a-3p, miR-29b, and miR-30d) repress it [PMID:25311867, PMID:32754259]. Functionally, intracellular LOXL4 promotes migration and invasion via amine-oxidase-dependent, hydrogen-peroxide-mediated activation of the FAK/Src pathway, and is packaged into exosomes/extracellular vesicles for transfer to recipient cells to drive angiogenesis and, in macrophages, STAT1-dependent PD-L1 induction that suppresses CD8+ T cell killing [PMID:25216702, PMID:30704479, PMID:38047403]. LOXL4 also engages discrete protein partners: it binds and reactivates wild-type p53 to trigger liver cancer cell death [PMID:30728460], and promotes ubiquitination and degradation of SOCS3 to sustain JAK2/STAT3 signaling and radiotherapy resistance in glioma [PMID:42134289]. In bladder cancer LOXL4 instead behaves as a tumor suppressor by antagonizing Ras-driven ERK activation [PMID:17456585].","teleology":[{"year":2001,"claim":"Established LOXL4 as a distinct lysyl oxidase family member, defining the catalytic copper-binding domain and SRCR architecture that distinguish it from its paralogs.","evidence":"cDNA cloning, sequence and genomic structure analysis","pmids":["11691588"],"confidence":"High","gaps":["No enzymatic activity measured directly on substrates","No tissue expression or functional role defined"]},{"year":2007,"claim":"Defined an early functional role by showing LOXL4 can act as a tumor suppressor through antagonism of the Ras/ERK pathway, framing LOXL4 function as context-dependent.","evidence":"Gene reintroduction, colony formation and ERK western blot in bladder cancer cells","pmids":["17456585"],"confidence":"Medium","gaps":["Mechanism of Ras antagonism not resolved","Whether amine oxidase activity is required is untested"]},{"year":2008,"claim":"Connected LOXL4 dysregulation in HNSCC to specific promoter elements and identified its perinuclear/cell-surface localization, hinting at adhesion/ECM functions rather than nuclear roles.","evidence":"Promoter deletion/reporter assays, EMSA, and immunocytochemistry in HNSCC cells","pmids":["18949373","18499440"],"confidence":"Medium","gaps":["TATA/SP1 binding inferred from EMSA, not validated by ChIP","Functional consequence of cell-surface localization not tested"]},{"year":2013,"claim":"Resolved how LOXL4 is induced by TGF-β1, demonstrating combinatorial Smad/AP-1 (JunB/Fra2) promoter control and confirming LOXL4 secretion and contribution to ECM assembly.","evidence":"Promoter mutagenesis, ChIP, reporter assays, and secretion assays in aortic endothelial cells","pmids":["23572561"],"confidence":"High","gaps":["Direct enzymatic cross-linking activity not measured","In vivo relevance of this transcriptional circuit untested"]},{"year":2014,"claim":"Linked LOXL4 to pro-tumorigenic signaling by showing it activates FAK/Src to enhance cell-ECM adhesion, migration and invasion, including via recombinant extracellular protein.","evidence":"Overexpression/RNAi, recombinant protein treatment, FAK/Src western blot, migration/invasion assays in gastric cancer","pmids":["25216702"],"confidence":"Medium","gaps":["Whether activity is intracellular or extracellular not disentangled here","Catalytic dependence not directly tested"]},{"year":2014,"claim":"Identified LOXL4 as a direct miR-193a-3p target whose suppression drives multidrug resistance via oxidative stress, establishing microRNA-mediated control of LOXL4.","evidence":"miRNA gain/loss, luciferase reporter, xenograft model in bladder cancer","pmids":["25311867"],"confidence":"Medium","gaps":["Molecular basis of oxidative-stress-mediated resistance not detailed","Direct LOXL4 enzymatic contribution not isolated"]},{"year":2017,"claim":"Revealed a suppressive ECM role in breast cancer, where LOXL4 loss increased collagen deposition, bundle thickening, and tumor growth, contrasting with its pro-invasive roles elsewhere.","evidence":"shRNA knockdown, mouse xenografts, second harmonic generation imaging, collagen-protein western blot","pmids":["28060764"],"confidence":"Medium","gaps":["Mechanism reconciling collagen suppression with cross-linking activity unclear","No biochemical cross-linking assay"]},{"year":2019,"claim":"Distinguished intracellular from extracellular LOXL4 function and showed amine-oxidase-dependent, H2O2-mediated FAK/Src activation drives migration, while exosomal transfer drives paracrine angiogenesis.","evidence":"Exosome transfer, domain-deletion mutants, shRNA, FAK/Src western blot, in vivo metastasis models in HCC","pmids":["30704479"],"confidence":"High","gaps":["Direct H2O2 measurement linking activity to FAK/Src not fully detailed","Mechanism of exosomal packaging unknown"]},{"year":2019,"claim":"Uncovered a non-catalytic protein-interaction function: LOXL4 binds the p53 basic domain to reactivate compromised wild-type p53 and induce liver cancer cell death.","evidence":"Genome-wide screen, Co-IP with domain mapping, xenograft, viability assays","pmids":["30728460"],"confidence":"High","gaps":["Whether amine oxidase activity contributes to p53 reactivation untested","Reciprocal structural validation of the interface absent"]},{"year":2020,"claim":"Placed LOXL4 within an epigenetic regulatory circuit, identifying it as a direct miR-29b/miR-30d target whose EZH2-mediated derepression promotes breast cancer progression.","evidence":"Dual-luciferase, ChIP, qRT-PCR, western blot, xenografts","pmids":["32754259"],"confidence":"High","gaps":["Downstream effector pathway from elevated LOXL4 not defined here","Catalytic requirement untested"]},{"year":2021,"claim":"Tested a vascular requirement and found LOXL4 dispensable for angiotensin II-induced aortic aneurysm, bounding its physiological role in vascular pathology.","evidence":"LOXL4 knockout mice with angiotensin II infusion and aneurysm assessment","pmids":["33807332"],"confidence":"Medium","gaps":["Negative result limited to one aneurysm model","Possible compensation by other LOX members not assessed"]},{"year":2023,"claim":"Established LOXL4 as the primary LOX activity driving pathological collagen cross-linking in lung fibrosis, with epistasis over LOXL2.","evidence":"Single and double Loxl2/Loxl4 knockout mice, pulmonary fibrosis model, collagen cross-linking and expression analysis","pmids":["37235663"],"confidence":"High","gaps":["Cell-type source of fibrotic LOXL4 not pinpointed","Reason LOXL4 loss reduces other LOX members unknown"]},{"year":2023,"claim":"Defined an immune-evasion mechanism in which EV-delivered LOXL4 activates STAT1/PD-L1 in macrophages to suppress CD8+ T cell killing in HCC.","evidence":"EV delivery, macrophage/T cell co-culture, orthotopic xenograft, STAT1/PD-L1 western blot","pmids":["38047403"],"confidence":"Medium","gaps":["How LOXL4 engages STAT1 mechanistically unclear","Catalytic dependence of STAT1 activation untested"]},{"year":2023,"claim":"Identified ZEB1, in its Zn2+-bound active form, as a transcriptional driver of LOXL4 coupling its expression to EMT and invasion.","evidence":"MutZEB1 (ΔZn) stable expression, invasion assays, RNA-Seq in MDA-MB-231 cells","pmids":["36910659"],"confidence":"Medium","gaps":["Direct ZEB1 occupancy at LOXL4 promoter not shown by ChIP","Functional contribution of induced LOXL4 to invasion not isolated"]},{"year":2025,"claim":"Showed post-translational control of LOXL4 by TGF-β1, which reduces LOXL4 protein via MEK/ERK-driven proteasomal degradation and N-glycosylation-linked secretion defects, revealing regulation opposing its transcriptional induction.","evidence":"Proteasome and MEK/ERK inhibition, ROS measurement, protein vs mRNA western blot, N-glycosylation analysis in MDA-MB-231 cells","pmids":["39862152"],"confidence":"Medium","gaps":["E3 ligase mediating degradation not identified","Reconciliation with TGF-β1 transcriptional induction in other contexts unresolved"]},{"year":2026,"claim":"Defined a LOXL4-SOCS3-STAT3 axis in which LOXL4 promotes SOCS3 ubiquitination/degradation to sustain JAK2/STAT3 signaling and radiotherapy resistance in glioma.","evidence":"Co-IP, mass spectrometry, RT-resistant cell models, DNA repair/apoptosis assays, orthotopic glioma model","pmids":["42134289"],"confidence":"Medium","gaps":["Whether LOXL4 acts as or recruits a ubiquitin ligase unknown","Catalytic requirement for SOCS3 degradation untested"]},{"year":null,"claim":"How LOXL4's single catalytic amine-oxidase activity is reconciled with its divergent context-dependent outputs—tumor suppression versus promotion, ECM cross-linking versus protein-partner signaling—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking catalytic activity to non-catalytic interactions","Structural basis of partner binding (p53, SOCS3) undetermined","In vivo determinants of tumor-suppressive vs oncogenic behavior unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,8,12]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,16]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8,13]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[7,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5,8,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]}],"complexes":[],"partners":["TP53","SOCS3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96JB6","full_name":"Lysyl oxidase homolog 4","aliases":["Lysyl oxidase-like protein 4","Lysyl oxidase-related protein C"],"length_aa":756,"mass_kda":84.5,"function":"Catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin, resulting in the formation of covalent cross-linkages, and the stabilization of collagen and elastin fibers","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/Q96JB6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LOXL4","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LOXL4","total_profiled":1310},"omim":[{"mim_id":"607318","title":"LYSYL OXIDASE-LIKE 4; LOXL4","url":"https://www.omim.org/entry/607318"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LOXL4"},"hgnc":{"alias_symbol":["FLJ21889","LOXC"],"prev_symbol":[]},"alphafold":{"accession":"Q96JB6","domains":[{"cath_id":"3.10.250.10","chopping":"32-144","consensus_level":"high","plddt":88.5652,"start":32,"end":144},{"cath_id":"3.10.250.10","chopping":"157-288","consensus_level":"medium","plddt":88.6336,"start":157,"end":288},{"cath_id":"3.10.250.10","chopping":"312-412","consensus_level":"medium","plddt":91.6695,"start":312,"end":412},{"cath_id":"3.10.250.10","chopping":"422-530","consensus_level":"high","plddt":91.2803,"start":422,"end":530},{"cath_id":"-","chopping":"536-752","consensus_level":"high","plddt":89.8127,"start":536,"end":752}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JB6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JB6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96JB6-F1-predicted_aligned_error_v6.png","plddt_mean":86.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LOXL4","jax_strain_url":"https://www.jax.org/strain/search?query=LOXL4"},"sequence":{"accession":"Q96JB6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96JB6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96JB6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96JB6"}},"corpus_meta":[{"pmid":"30704479","id":"PMC_30704479","title":"Exosome-mediated secretion of LOXL4 promotes hepatocellular carcinoma cell invasion and metastasis.","date":"2019","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30704479","citation_count":193,"is_preprint":false},{"pmid":"17456585","id":"PMC_17456585","title":"LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17456585","citation_count":94,"is_preprint":false},{"pmid":"23572561","id":"PMC_23572561","title":"LOXL4 is induced by transforming growth factor β1 through Smad and JunB/Fra2 and contributes to vascular matrix remodeling.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23572561","citation_count":78,"is_preprint":false},{"pmid":"25311867","id":"PMC_25311867","title":"miR-193a-3p regulates the multi-drug resistance of bladder cancer by targeting the LOXL4 gene and the oxidative stress pathway.","date":"2014","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25311867","citation_count":75,"is_preprint":false},{"pmid":"11691588","id":"PMC_11691588","title":"A novel human lysyl oxidase-like gene (LOXL4) on chromosome 10q24 has an altered scavenger receptor cysteine rich domain.","date":"2001","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/11691588","citation_count":73,"is_preprint":false},{"pmid":"32754259","id":"PMC_32754259","title":"EZH2-mediated Epigenetic Silencing of miR-29/miR-30 targets LOXL4 and contributes to Tumorigenesis, Metastasis, and Immune Microenvironment Remodeling in Breast Cancer.","date":"2020","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/32754259","citation_count":71,"is_preprint":false},{"pmid":"25216702","id":"PMC_25216702","title":"Lysyl oxidase-like 4 (LOXL4) promotes proliferation and metastasis of gastric cancer via FAK/Src pathway.","date":"2014","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/25216702","citation_count":56,"is_preprint":false},{"pmid":"28060764","id":"PMC_28060764","title":"LOXL4 knockdown enhances tumor growth and lung metastasis through collagen-dependent extracellular matrix changes in triple-negative breast cancer.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/28060764","citation_count":48,"is_preprint":false},{"pmid":"37235663","id":"PMC_37235663","title":"LOXL4, but not LOXL2, is the critical determinant of pathological collagen cross-linking and fibrosis in the lung.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/37235663","citation_count":42,"is_preprint":false},{"pmid":"30728460","id":"PMC_30728460","title":"Derepression of LOXL4 inhibits liver cancer growth by reactivating compromised p53.","date":"2019","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/30728460","citation_count":42,"is_preprint":false},{"pmid":"17354256","id":"PMC_17354256","title":"Selective upregulation and amplification of the lysyl oxidase like-4 (LOXL4) gene in head and neck squamous cell carcinoma.","date":"2007","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/17354256","citation_count":37,"is_preprint":false},{"pmid":"30993701","id":"PMC_30993701","title":"Downregulation of lysyl oxidase-like 4 LOXL4 by miR-135a-5p promotes lung cancer progression in vitro and in vivo.","date":"2019","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30993701","citation_count":31,"is_preprint":false},{"pmid":"18499440","id":"PMC_18499440","title":"LOXL4 is a selectively expressed candidate diagnostic antigen in head and neck cancer.","date":"2008","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/18499440","citation_count":28,"is_preprint":false},{"pmid":"24357854","id":"PMC_24357854","title":"Identification of the involvement of LOXL4 in generation of keratocystic odontogenic tumors by RNA-Seq analysis.","date":"2013","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/24357854","citation_count":21,"is_preprint":false},{"pmid":"21115907","id":"PMC_21115907","title":"LOXL4 as a selective molecular marker in primary and metastatic head/neck carcinoma.","date":"2010","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/21115907","citation_count":17,"is_preprint":false},{"pmid":"38047403","id":"PMC_38047403","title":"LOXL4 Shuttled by Tumor Cells-derived Extracellular Vesicles Promotes Immune Escape in Hepatocellular Carcinoma by Activating the STAT1/PD-L1 Axis.","date":"2023","source":"Journal of immunotherapy (Hagerstown, Md. : 1997)","url":"https://pubmed.ncbi.nlm.nih.gov/38047403","citation_count":13,"is_preprint":false},{"pmid":"30900087","id":"PMC_30900087","title":"Clinical significance of LOXL4 expression and features of LOXL4-associated protein-protein interaction network in esophageal squamous cell carcinoma.","date":"2019","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/30900087","citation_count":12,"is_preprint":false},{"pmid":"37197500","id":"PMC_37197500","title":"miR-183-5p regulates ECM and EMT to promote non-small cell lung cancer progression by targeting LOXL4.","date":"2023","source":"Journal of thoracic disease","url":"https://pubmed.ncbi.nlm.nih.gov/37197500","citation_count":11,"is_preprint":false},{"pmid":"35433959","id":"PMC_35433959","title":"Overexpression of miR-328-5p influences cell growth and migration to promote NSCLC progression by targeting LOXL4.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35433959","citation_count":10,"is_preprint":false},{"pmid":"33807332","id":"PMC_33807332","title":"LOXL4 Abrogation Does Not Exaggerate Angiotensin II-Induced Thoracic or Abdominal Aortic Aneurysm in Mice.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/33807332","citation_count":9,"is_preprint":false},{"pmid":"36910659","id":"PMC_36910659","title":"LOXL1 and LOXL4 are novel target genes of the Zn2+-bound form of ZEB1 and play a crucial role in the acceleration of invasive events in triple-negative breast cancer cells.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36910659","citation_count":9,"is_preprint":false},{"pmid":"18949373","id":"PMC_18949373","title":"Functional analysis of the 5' flanking domain of the LOXL4 gene in head and neck squamous cell carcinoma cells.","date":"2008","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/18949373","citation_count":9,"is_preprint":false},{"pmid":"35113007","id":"PMC_35113007","title":"Long non-coding RNA AGAP2-AS1 promotes cell proliferation and invasion through regulating miR-193a-3p/LOXL4 axis in laryngeal squamous cell carcinoma.","date":"2022","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/35113007","citation_count":8,"is_preprint":false},{"pmid":"29438669","id":"PMC_29438669","title":"Trans-suppression of host CDH3 and LOXL4 genes during Cryptosporidium parvum infection involves nuclear delivery of parasite Cdg7_FLc_1000 RNA.","date":"2018","source":"International journal for parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/29438669","citation_count":8,"is_preprint":false},{"pmid":"38737700","id":"PMC_38737700","title":"The dual role of LOXL4 in the pathogenesis and development of human malignant tumors: a narrative review.","date":"2024","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38737700","citation_count":7,"is_preprint":false},{"pmid":"26138381","id":"PMC_26138381","title":"Differential expression of LOXL4 in normal and tumour tissue samples of laryngeal squamous cell carcinoma.","date":"2016","source":"Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/26138381","citation_count":7,"is_preprint":false},{"pmid":"29532123","id":"PMC_29532123","title":"Collagen XVIII and LOXL-4 polymorphisms in women with and without advanced pelvic organ prolapse.","date":"2018","source":"International urogynecology journal","url":"https://pubmed.ncbi.nlm.nih.gov/29532123","citation_count":6,"is_preprint":false},{"pmid":"40795623","id":"PMC_40795623","title":"LOXL4, CREB5 and steroid hormone biosynthesis pathways are involved in type 1 diabetes with polycystic ovary-like changes.","date":"2025","source":"European journal of obstetrics, gynecology, and reproductive biology","url":"https://pubmed.ncbi.nlm.nih.gov/40795623","citation_count":2,"is_preprint":false},{"pmid":"41203182","id":"PMC_41203182","title":"LNC511 inhibits lung cancer progression by modulating the miR-625/LOXL4/Wnt/β-catenin pathway.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/41203182","citation_count":1,"is_preprint":false},{"pmid":"34565340","id":"PMC_34565340","title":"LAMA2 and LOXL4 are candidate FSGS genes.","date":"2021","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/34565340","citation_count":0,"is_preprint":false},{"pmid":"39862152","id":"PMC_39862152","title":"Bortezomib suppresses TGF-β1-mediated LOXL4 reduction through the inhibition of MEK/ERK pathways in MDA-MB-231 cells.","date":"2025","source":"Journal of receptor and signal transduction 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immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42134289","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.06.25333006","title":"Genome-Wide Meta-Analysis Identifies Genetic Risk Loci for Mono- and Polyneuropathies in 983,477 Individuals","date":"2025-08-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.06.25333006","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.28.656636","title":"Expression of Lysyl Oxidase Family Enzymes During Human Endometrial Decidualization","date":"2025-05-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.28.656636","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":20891,"output_tokens":4512,"usd":0.065176,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12480,"output_tokens":4906,"usd":0.092525,"stage2_stop_reason":"end_turn"},"total_usd":0.157701,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"LOXL4 was identified as a novel lysyl oxidase family member with a conserved C-terminal copper-binding site, lysyl and tyrosyl residues, and a cytokine receptor-like domain. It contains four N-terminal SRCR domains, one of which has a unique 13 amino acid insertion encoded by a short exon not present in LOXL2 or LOXL3. The gene is located on chromosome 10q24 and spans 14 exons.\",\n      \"method\": \"cDNA cloning, sequence analysis, genomic structure determination\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct molecular characterization of gene/protein structure, foundational identification paper\",\n      \"pmids\": [\"11691588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Reintroduction of LOXL4 into human bladder cancer cells decreased colony formation ability and antagonized Ras in activating the ERK signaling pathway, establishing LOXL4 as a functional tumor suppressor acting through inhibition of the Ras/ERK pathway.\",\n      \"method\": \"Gene reintroduction (overexpression), colony formation assay, ERK signaling western blot, promoter methylation analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment with defined pathway readout (Ras/ERK), single lab, two orthogonal methods\",\n      \"pmids\": [\"17456585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LOXL4 gene overexpression in HNSCC cells is driven by de novo transcription, with TATA (-25) and SP1 (-181) binding sites showing increased nuclear extract binding activity in HNSCC cells compared to normal epithelial cells, indicating these transcription factors regulate LOXL4 upregulation.\",\n      \"method\": \"Promoter deletion analysis, reporter gene assays, DNA-binding (EMSA) experiments with nuclear extracts\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter analysis with DNA-binding experiments, single lab, multiple constructs tested\",\n      \"pmids\": [\"18949373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LOXL4 protein in cultured primary hypopharyngeal HTB-43 carcinoma cells localizes perinuclearly and at the cell surface, but not in the nucleus, suggesting cell surface-associated functions in tumor cell adhesion and extracellular matrix interactions.\",\n      \"method\": \"Immunocytochemistry in cultured HNSCC cells with LOXL4-specific antibody\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct subcellular localization by immunocytochemistry, replicated across HNSCC studies, single method\",\n      \"pmids\": [\"18499440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGF-β1 induces LOXL4 expression in aortic endothelial cells via a mechanism requiring both a distal AP-1 site and a Smad binding element in the LOXL4 promoter. Functional cooperation between Smad proteins and the AP-1 complex composed of JunB/Fra2 mediates TGF-β1 induction, involving ERK-dependent phosphorylation of Fra2. LOXL4 is extracellularly secreted and contributes to ECM deposition and assembly.\",\n      \"method\": \"Promoter deletion mapping, mutagenesis analysis, reporter gene assays, western blotting for ERK phosphorylation, chromatin immunoprecipitation, secretion assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter mutagenesis with functional validation, multiple orthogonal methods (ChIP, reporter assay, mutagenesis), single rigorous study\",\n      \"pmids\": [\"23572561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL4 promotes gastric cancer cell proliferation, migration and invasion, and activates the FAK/Src pathway to enhance cell-extracellular matrix adhesion. Recombinant human LOXL4 protein also promoted GC cell proliferation and migration, indicating extracellular LOXL4 activity.\",\n      \"method\": \"Overexpression, RNA interference, recombinant protein treatment, western blot for FAK/Src pathway, migration/invasion assays\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional gain/loss-of-function with defined pathway readout, recombinant protein validation, single lab\",\n      \"pmids\": [\"25216702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LOXL4 is a direct target of miR-193a-3p; miR-193a-3p promotes multi-drug resistance in bladder cancer cells through suppression of LOXL4, and this resistance is mediated downstream via the Oxidative Stress pathway.\",\n      \"method\": \"miRNA overexpression/inhibition, luciferase reporter assay, xenograft tumor model, oxidative stress pathway analysis\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase assay plus in vivo xenograft, single lab, two orthogonal methods\",\n      \"pmids\": [\"25311867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LOXL4 knockdown in triple-negative breast cancer cells increased primary tumor growth and lung colonization in mouse xenograft models, accompanied by increased collagen I and IV, lysine hydroxylase 1 and 2, and prolyl 4-hydroxylase subunit alpha 1 and 2 levels. Second harmonic generation imaging showed LOXL4 knockdown resulted in thickening of collagen bundles, indicating LOXL4 suppresses collagen synthesis, deposition, and structural changes in the ECM.\",\n      \"method\": \"shRNA knockdown, mouse xenograft model, second harmonic generation imaging, western blotting for collagen-related proteins\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional KD with defined ECM phenotype, multiple orthogonal methods (SHG imaging, western blot), single lab\",\n      \"pmids\": [\"28060764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HCC-derived exosomes transfer LOXL4 between HCC cells and to HUVECs. Intracellular (but not extracellular) LOXL4 promotes cell migration by activating the FAK/Src pathway dependent on its amine oxidase activity through a hydrogen peroxide-mediated mechanism. Exosome-transferred LOXL4 promotes angiogenesis via a paracrine mechanism.\",\n      \"method\": \"Exosome isolation and characterization, overexpression/shRNA knockdown, deletion mutants including amine oxidase domain mutants, western blot for FAK/Src, migration assays, in vivo metastasis models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (domain deletion mutants, exosome transfer, in vivo models, pathway western blot), single lab with rigorous controls\",\n      \"pmids\": [\"30704479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"5-azacytidine (5-aza-CR) induces LOXL4 upregulation in liver cancer cells, and LOXL4 subsequently binds the basic domain of p53 via its low-isoelectric point region, inducing reactivation of compromised wild-type p53 and resulting in cell death. The LOXL4-p53 interaction was identified through genome-wide screening.\",\n      \"method\": \"Genome-wide screen, co-immunoprecipitation (LOXL4-p53 binding), domain mapping, xenograft tumor model, cell viability assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — protein-protein interaction (Co-IP with domain mapping), functional in vitro and in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30728460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EZH2 inhibition enhances miR-30d and miR-29b transcription via promoter binding, reducing LOXL4 expression. LOXL4 was identified as a direct target of miR-29b and miR-30d (validated by dual-luciferase reporter assay and ChIP). EZH2-mediated epigenetic silencing of miR-29b/miR-30d results in elevated LOXL4, promoting breast cancer cell proliferation, migration, and metastasis.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation, qRT-PCR, western blotting, xenograft experiments\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct target validation by luciferase+ChIP, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32754259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic ablation of LOXL4 in mice did not induce more severe thoracic or abdominal aortic aneurysm compared to wild-type mice under angiotensin II infusion, indicating LOXL4 does not play a major role in angiotensin II-induced aortic aneurysm development.\",\n      \"method\": \"LOXL4 knockout mouse generation, angiotensin II subcutaneous infusion, aortic aneurysm assessment\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean knockout mouse model with defined phenotypic readout (negative result), single lab, single study\",\n      \"pmids\": [\"33807332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Genetic ablation of LOXL4 (but not LOXL2) markedly disrupts pathological collagen cross-linking and fibrosis in the lung. Combined knockout of Loxl2 and Loxl4 does not offer additive antifibrotic effects over Loxl4 deletion alone, and LOXL4 deficiency decreases expression of other LOX family members including Loxl2, establishing LOXL4 as the primary LOX activity underlying pathological collagen cross-linking in lung fibrosis.\",\n      \"method\": \"Genetic knockout mice (Loxl2 KO, Loxl4 KO, double KO), pulmonary fibrosis model, collagen cross-linking analysis, gene expression analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockouts with quantitative collagen cross-linking readout, comparison of single vs double KO, rigorous epistasis analysis\",\n      \"pmids\": [\"37235663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LOXL4 shuttled by tumor cell-derived extracellular vesicles is delivered into macrophages, where it activates STAT1 signaling to induce PD-L1 expression, suppressing CD8+ T cell killing activity and promoting immune escape in hepatocellular carcinoma.\",\n      \"method\": \"EV isolation and delivery, in vitro macrophage/CD8+ T cell co-culture assay, in vivo orthotopic xenograft model, western blot for STAT1/PD-L1\",\n      \"journal\": \"Journal of immunotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mechanism (EV delivery → STAT1/PD-L1 axis) validated in vitro and in vivo, single lab, multiple methods\",\n      \"pmids\": [\"38047403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZEB1 (in its Zn2+-bound active form) acts as a transcription factor that drives expression of LOXL1 and LOXL4. Mutation of the Zn-finger motifs of ZEB1 (MutZEB1 ΔZn) leads to significant downregulation of LOXL1 and LOXL4, loss of EMT, and stalled invasion in MDA-MB-231 cells.\",\n      \"method\": \"Stable expression of MutZEB1 (ΔZn) in MDA-MB-231 cells, invasion assays, RNA-Seq analysis\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional genetic approach with defined invasion phenotype and transcriptomic validation, single lab\",\n      \"pmids\": [\"36910659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TGF-β1 decreases LOXL4 protein (but not mRNA) expression in MDA-MB-231 breast cancer cells via proteasomal degradation through MEK/ERK pathway activation. Bortezomib (proteasomal inhibitor) suppresses TGF-β1-mediated LOXL4 reduction and inhibits TGF-β1-induced MEK/ERK pathways. N-glycosylation dysregulation is involved in reduction of LOXL4 secretion.\",\n      \"method\": \"Proteasomal inhibitor treatment, MEK/ERK inhibition, ROS measurement, western blotting for LOXL4 protein vs. mRNA levels, N-glycosylation analysis\",\n      \"journal\": \"Journal of receptor and signal transduction research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic dissection of post-translational regulation using pharmacological inhibitors and mRNA vs. protein comparison, single lab\",\n      \"pmids\": [\"39862152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LOXL4 promotes ubiquitination and degradation of SOCS3 (suppressor of cytokine signaling 3), relieving SOCS3-mediated inhibition of JAK2 and leading to sustained STAT3 activation. This LOXL4-SOCS3-STAT3 axis enhances DNA damage repair, inhibits apoptosis, and fosters an immunosuppressive tumor microenvironment, driving radiotherapy resistance in glioma.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, stable RT-resistant cell models, functional assays for DNA repair and apoptosis, orthotopic glioma mouse model\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and mass spectrometry identify SOCS3 as binding partner/substrate, in vivo validation, single lab\",\n      \"pmids\": [\"42134289\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LOXL4 is a secreted, copper-dependent amine oxidase that catalyzes collagen and elastin cross-linking to regulate extracellular matrix homeostasis, and is the primary LOX family member responsible for pathological collagen cross-linking in lung fibrosis; intracellularly, LOXL4 promotes cell migration and invasion via its amine oxidase activity through hydrogen peroxide-mediated activation of the FAK/Src pathway, can bind and reactivate wild-type p53 to suppress liver cancer, and can promote ubiquitination and degradation of SOCS3 to activate JAK2/STAT3 signaling; its expression is transcriptionally induced by TGF-β1 through cooperative Smad/JunB-Fra2 (AP-1) signaling and by the Zn2+-activated transcription factor ZEB1, while being subject to proteasomal degradation downstream of TGF-β1/MEK/ERK, and is regulated by multiple microRNAs (miR-193a-3p, miR-135a-5p, miR-183-5p, miR-328-5p, miR-29b, miR-30d); LOXL4 can also be packaged into exosomes/extracellular vesicles and transferred to recipient cells (including macrophages and endothelial cells) to promote angiogenesis and immune escape via STAT1/PD-L1 activation, and acts as a tumor suppressor in bladder cancer by inhibiting the Ras/ERK pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LOXL4 is a secreted, copper-dependent lysyl oxidase family member that catalyzes extracellular matrix collagen cross-linking and, beyond this canonical role, exerts context-dependent control over tumor cell signaling, immune evasion, and angiogenesis [#0, #12]. Structurally it is defined by a conserved C-terminal copper-binding catalytic domain plus four N-terminal SRCR domains, including one bearing a unique 13-amino-acid insertion that distinguishes it from LOXL2 and LOXL3 [#0]. In the lung, genetic ablation studies establish LOXL4 as the dominant LOX family activity driving pathological collagen cross-linking in fibrosis, with LOXL4 loss reducing fibrosis more strongly than LOXL2 loss and even lowering expression of other LOX members [#12]. Its expression is transcriptionally induced by TGF-\\u03b21 through cooperative Smad and JunB/Fra2 (AP-1) signaling at the LOXL4 promoter and by the Zn2+-activated transcription factor ZEB1, which couples LOXL4 to EMT and invasion [#4, #14], while at the protein level TGF-\\u03b21 can conversely drive its proteasomal degradation through MEK/ERK [#15], and multiple microRNAs (including miR-193a-3p, miR-29b, and miR-30d) repress it [#6, #10]. Functionally, intracellular LOXL4 promotes migration and invasion via amine-oxidase-dependent, hydrogen-peroxide-mediated activation of the FAK/Src pathway, and is packaged into exosomes/extracellular vesicles for transfer to recipient cells to drive angiogenesis and, in macrophages, STAT1-dependent PD-L1 induction that suppresses CD8+ T cell killing [#5, #8, #13]. LOXL4 also engages discrete protein partners: it binds and reactivates wild-type p53 to trigger liver cancer cell death [#9], and promotes ubiquitination and degradation of SOCS3 to sustain JAK2/STAT3 signaling and radiotherapy resistance in glioma [#16]. In bladder cancer LOXL4 instead behaves as a tumor suppressor by antagonizing Ras-driven ERK activation [#1].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established LOXL4 as a distinct lysyl oxidase family member, defining the catalytic copper-binding domain and SRCR architecture that distinguish it from its paralogs.\",\n      \"evidence\": \"cDNA cloning, sequence and genomic structure analysis\",\n      \"pmids\": [\"11691588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic activity measured directly on substrates\", \"No tissue expression or functional role defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined an early functional role by showing LOXL4 can act as a tumor suppressor through antagonism of the Ras/ERK pathway, framing LOXL4 function as context-dependent.\",\n      \"evidence\": \"Gene reintroduction, colony formation and ERK western blot in bladder cancer cells\",\n      \"pmids\": [\"17456585\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Ras antagonism not resolved\", \"Whether amine oxidase activity is required is untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected LOXL4 dysregulation in HNSCC to specific promoter elements and identified its perinuclear/cell-surface localization, hinting at adhesion/ECM functions rather than nuclear roles.\",\n      \"evidence\": \"Promoter deletion/reporter assays, EMSA, and immunocytochemistry in HNSCC cells\",\n      \"pmids\": [\"18949373\", \"18499440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TATA/SP1 binding inferred from EMSA, not validated by ChIP\", \"Functional consequence of cell-surface localization not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved how LOXL4 is induced by TGF-\\u03b21, demonstrating combinatorial Smad/AP-1 (JunB/Fra2) promoter control and confirming LOXL4 secretion and contribution to ECM assembly.\",\n      \"evidence\": \"Promoter mutagenesis, ChIP, reporter assays, and secretion assays in aortic endothelial cells\",\n      \"pmids\": [\"23572561\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic cross-linking activity not measured\", \"In vivo relevance of this transcriptional circuit untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked LOXL4 to pro-tumorigenic signaling by showing it activates FAK/Src to enhance cell-ECM adhesion, migration and invasion, including via recombinant extracellular protein.\",\n      \"evidence\": \"Overexpression/RNAi, recombinant protein treatment, FAK/Src western blot, migration/invasion assays in gastric cancer\",\n      \"pmids\": [\"25216702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether activity is intracellular or extracellular not disentangled here\", \"Catalytic dependence not directly tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified LOXL4 as a direct miR-193a-3p target whose suppression drives multidrug resistance via oxidative stress, establishing microRNA-mediated control of LOXL4.\",\n      \"evidence\": \"miRNA gain/loss, luciferase reporter, xenograft model in bladder cancer\",\n      \"pmids\": [\"25311867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of oxidative-stress-mediated resistance not detailed\", \"Direct LOXL4 enzymatic contribution not isolated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a suppressive ECM role in breast cancer, where LOXL4 loss increased collagen deposition, bundle thickening, and tumor growth, contrasting with its pro-invasive roles elsewhere.\",\n      \"evidence\": \"shRNA knockdown, mouse xenografts, second harmonic generation imaging, collagen-protein western blot\",\n      \"pmids\": [\"28060764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism reconciling collagen suppression with cross-linking activity unclear\", \"No biochemical cross-linking assay\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Distinguished intracellular from extracellular LOXL4 function and showed amine-oxidase-dependent, H2O2-mediated FAK/Src activation drives migration, while exosomal transfer drives paracrine angiogenesis.\",\n      \"evidence\": \"Exosome transfer, domain-deletion mutants, shRNA, FAK/Src western blot, in vivo metastasis models in HCC\",\n      \"pmids\": [\"30704479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct H2O2 measurement linking activity to FAK/Src not fully detailed\", \"Mechanism of exosomal packaging unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Uncovered a non-catalytic protein-interaction function: LOXL4 binds the p53 basic domain to reactivate compromised wild-type p53 and induce liver cancer cell death.\",\n      \"evidence\": \"Genome-wide screen, Co-IP with domain mapping, xenograft, viability assays\",\n      \"pmids\": [\"30728460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether amine oxidase activity contributes to p53 reactivation untested\", \"Reciprocal structural validation of the interface absent\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed LOXL4 within an epigenetic regulatory circuit, identifying it as a direct miR-29b/miR-30d target whose EZH2-mediated derepression promotes breast cancer progression.\",\n      \"evidence\": \"Dual-luciferase, ChIP, qRT-PCR, western blot, xenografts\",\n      \"pmids\": [\"32754259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effector pathway from elevated LOXL4 not defined here\", \"Catalytic requirement untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested a vascular requirement and found LOXL4 dispensable for angiotensin II-induced aortic aneurysm, bounding its physiological role in vascular pathology.\",\n      \"evidence\": \"LOXL4 knockout mice with angiotensin II infusion and aneurysm assessment\",\n      \"pmids\": [\"33807332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result limited to one aneurysm model\", \"Possible compensation by other LOX members not assessed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established LOXL4 as the primary LOX activity driving pathological collagen cross-linking in lung fibrosis, with epistasis over LOXL2.\",\n      \"evidence\": \"Single and double Loxl2/Loxl4 knockout mice, pulmonary fibrosis model, collagen cross-linking and expression analysis\",\n      \"pmids\": [\"37235663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type source of fibrotic LOXL4 not pinpointed\", \"Reason LOXL4 loss reduces other LOX members unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined an immune-evasion mechanism in which EV-delivered LOXL4 activates STAT1/PD-L1 in macrophages to suppress CD8+ T cell killing in HCC.\",\n      \"evidence\": \"EV delivery, macrophage/T cell co-culture, orthotopic xenograft, STAT1/PD-L1 western blot\",\n      \"pmids\": [\"38047403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How LOXL4 engages STAT1 mechanistically unclear\", \"Catalytic dependence of STAT1 activation untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified ZEB1, in its Zn2+-bound active form, as a transcriptional driver of LOXL4 coupling its expression to EMT and invasion.\",\n      \"evidence\": \"MutZEB1 (\\u0394Zn) stable expression, invasion assays, RNA-Seq in MDA-MB-231 cells\",\n      \"pmids\": [\"36910659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ZEB1 occupancy at LOXL4 promoter not shown by ChIP\", \"Functional contribution of induced LOXL4 to invasion not isolated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed post-translational control of LOXL4 by TGF-\\u03b21, which reduces LOXL4 protein via MEK/ERK-driven proteasomal degradation and N-glycosylation-linked secretion defects, revealing regulation opposing its transcriptional induction.\",\n      \"evidence\": \"Proteasome and MEK/ERK inhibition, ROS measurement, protein vs mRNA western blot, N-glycosylation analysis in MDA-MB-231 cells\",\n      \"pmids\": [\"39862152\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase mediating degradation not identified\", \"Reconciliation with TGF-\\u03b21 transcriptional induction in other contexts unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a LOXL4-SOCS3-STAT3 axis in which LOXL4 promotes SOCS3 ubiquitination/degradation to sustain JAK2/STAT3 signaling and radiotherapy resistance in glioma.\",\n      \"evidence\": \"Co-IP, mass spectrometry, RT-resistant cell models, DNA repair/apoptosis assays, orthotopic glioma model\",\n      \"pmids\": [\"42134289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LOXL4 acts as or recruits a ubiquitin ligase unknown\", \"Catalytic requirement for SOCS3 degradation untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LOXL4's single catalytic amine-oxidase activity is reconciled with its divergent context-dependent outputs\\u2014tumor suppression versus promotion, ECM cross-linking versus protein-partner signaling\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking catalytic activity to non-catalytic interactions\", \"Structural basis of partner binding (p53, SOCS3) undetermined\", \"In vivo determinants of tumor-suppressive vs oncogenic behavior unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 8, 12]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [7, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5, 8, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TP53\", \"SOCS3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}