Affinage

LOX

Protein-lysine 6-oxidase · UniProt P28300

Round 2 corrected
Length
417 aa
Mass
46.9 kDa
Annotated
2026-04-28
130 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LOX (protein-lysine 6-oxidase) is a secreted copper- and lysyl-tyrosylquinone (LTQ)-dependent amine oxidase that catalyzes oxidative deamination of lysine residues in collagen and elastin, generating reactive aldehydes that drive covalent crosslinks essential for extracellular matrix (ECM) structural integrity (PMID:12577300, PMID:25979340). Synthesized as a ~50 kDa proenzyme, LOX is proteolytically processed to the ~30 kDa active form by BMP-1/procollagen C-proteinase, a step facilitated by cellular fibronectin scaffolding and fibulin-4-mediated recruitment to tropoelastin (PMID:8636136, PMID:15843371, PMID:19855011). Beyond ECM crosslinking, LOX generates H₂O₂ as an enzymatic byproduct that activates FAK/Src signaling to promote cell migration, crosslinks collagen IV at premetastatic niches to recruit CD11b⁺ myeloid cells, and transcriptionally activates SNAI2 to drive epithelial–mesenchymal transition; its expression is induced by HIF-1α/HIF-2α under hypoxia, TGFβ via Smad and JNK/AP-1 pathways, and IL-17/ERK/AP-1, while LKB1–mTOR signaling negatively regulates it (PMID:16357151, PMID:19111879, PMID:27029493, PMID:20026874, PMID:20956321, PMID:32649012). Heterozygous loss-of-function mutations in the LOX catalytic domain cause familial thoracic aortic aneurysm and dissection (TAAD) due to insufficient elastin and collagen crosslinking (PMID:26838787, PMID:27432961).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    Identifying the protease that activates LOX resolved how the secreted proenzyme acquires catalytic competence: BMP-1/procollagen C-proteinase cleaves the 50 kDa pro-LOX to the 30 kDa mature enzyme extracellularly.

    Evidence In vitro cleavage assays with recombinant BMP-1, N-terminal sequencing, and peptide inhibitor blockade in fibroblast cultures

    PMID:8636136

    Open questions at the time
    • Contribution of MMP-2-mediated alternative cleavage to LOX processing in vivo is unclear
    • Kinetics of BMP-1-dependent processing in different tissue contexts not established
  2. 2003 High

    Biochemical reconstitution of LOX catalytic activity defined the enzyme's core mechanism—copper and the unique LTQ cofactor catalyze oxidative deamination of lysine residues in elastin, collagen, and even histone H1, while the propeptide domain suppresses activity.

    Evidence In vitro enzyme activity assays with cofactor identification and multiple substrate characterization; domain analysis across the LOX family

    PMID:12577300 PMID:12686136

    Open questions at the time
    • Structural basis (crystal structure) of the LOX catalytic domain remains unresolved
    • Physiological relevance of histone H1 as a LOX substrate in vivo not established
  3. 2004 High

    Demonstration that LOX is silenced by promoter methylation and LOH in gastric cancers, and that its re-expression suppresses tumorigenesis, established LOX (via its propeptide) as a tumor suppressor—an unexpected role distinct from ECM crosslinking.

    Evidence Bisulfite sequencing, LOX re-expression in LOX-silenced gastric cancer cells, colony formation and xenograft assays

    PMID:15374948

    Open questions at the time
    • Whether tumor-suppressive activity resides in the propeptide versus the catalytic domain was not fully resolved in this study
    • Generalizability across cancer types was unclear at this point
  4. 2005 High

    Identifying cellular fibronectin as a high-affinity LOX scaffold (Kd ~2.5 nM) that is required for proenzyme processing explained how LOX activation is spatially regulated within the ECM, and separately, demonstrating that LOX-generated H₂O₂ activates FAK/Src to drive breast cancer cell migration linked its enzymatic byproduct to oncogenic signaling.

    Evidence Yeast two-hybrid, GST pulldown, Kd measurements, FN-null fibroblast LOX processing assay; BAPN/catalase experiments with FAK/Src phosphorylation in breast cancer cells

    PMID:15843371 PMID:16357151

    Open questions at the time
    • How fibronectin-scaffolded LOX is handed off to specific collagen or elastin substrates is unknown
    • Whether H₂O₂-mediated signaling is a general feature of LOX activity in non-cancer tissues has not been tested
  5. 2009 High

    Multiple 2009 studies collectively established LOX as a central effector of hypoxia-driven metastasis and vascular integrity: LOX crosslinks collagen IV at premetastatic niches to recruit CD11b⁺ myeloid cells; HIF-1 directly transcribes LOX to repress E-cadherin and drive EMT; and fibulin-4 recruits LOX onto tropoelastin—loss of which causes aortic aneurysm in mice.

    Evidence Mouse metastasis models with BAPN, ChIP/reporter assays for HIF-1–LOX, fibulin-4-LOX interaction assays, conditional FBLN4-knockout mice, Lox-/- osteoblast characterization

    PMID:19111879 PMID:19458888 PMID:19855011 PMID:20026874

    Open questions at the time
    • Direct structural basis of fibulin-4–LOX propeptide interaction not solved
    • Relative contribution of LOX versus LOXL2 to hypoxia-driven EMT not disentangled
    • Osteoblast differentiation defect mechanism (cell-autonomous vs. ECM-mediated) not resolved
  6. 2010 High

    Placing LOX downstream of LKB1–mTOR–HIF-1α in lung cancer established that metabolic tumor suppressor pathways converge on LOX to regulate collagen deposition and β1-integrin-dependent invasiveness.

    Evidence LKB1 knockdown/overexpression, mTOR and HIF-1α inhibitors, BAPN treatment in LKB1-deficient mouse tumors

    PMID:20956321

    Open questions at the time
    • Whether LKB1–mTOR–HIF-1α regulation of LOX operates in non-malignant tissues is unknown
  7. 2011 High

    TGFβ was shown to induce LOX through dual Smad and JNK/AP-1 pathways, while LOX–SRC signaling was validated as a targetable axis in colorectal cancer, broadening both the upstream regulators and downstream effectors of LOX in disease.

    Evidence Smad/JNK inhibitor studies in trabecular meshwork cells; LOX gain/loss of function with dasatinib in CRC xenografts

    PMID:21282564 PMID:21546528

    Open questions at the time
    • Whether SRC activation requires LOX catalytic activity (H₂O₂) or a non-enzymatic mechanism is not resolved for CRC
    • Relative contribution of Smad vs. JNK/AP-1 in specific tissues not quantified
  8. 2014 Medium

    A naturally occurring LOX propeptide polymorphism (Arg158Gln) was shown to abolish the tumor-suppressive activity of LOX-PP, while VSMC-targeted LOX overexpression reduced neointimal hyperplasia, demonstrating that both the propeptide and the catalytic domain have distinct, tissue-specific protective roles.

    Evidence Xenograft assays with LOX-PP variants; SM22α-LOX transgenic mice with carotid ligation

    PMID:19654310 PMID:24990180

    Open questions at the time
    • Molecular mechanism by which LOX-PP exerts tumor suppression (target identification) is incomplete
    • Whether VSMC anti-proliferative effect is catalytic activity–dependent or propeptide-mediated is not resolved
  9. 2015 High

    Functional studies in tendon and skeletal muscle confirmed that LOX catalytic activity is required for ordered collagen fibrillogenesis and demonstrated a TGFβ–LOX feedback loop that balances myofiber and connective tissue development.

    Evidence BAPN-treated human tenocyte constructs with EM/mechanical testing; conditional Lox-knockout mice with myofiber/MCT quantification

    PMID:25715398 PMID:25979340

    Open questions at the time
    • Whether LOX acts on specific collagen types (e.g. collagen V) in tendon is not resolved
    • Identity of the myofiber-derived signal that attenuates TGFβ through LOX is unclear
  10. 2016 High

    Human genetic studies proved LOX haploinsufficiency causes TAAD: multiple families with heterozygous catalytic-domain mutations showed reduced enzymatic activity, and CRISPR knock-in of a human variant (Met298Arg) recapitulated aortic aneurysm in mice, establishing LOX as a TAAD-causative gene.

    Evidence Exome sequencing and co-segregation in families, lysyl oxidase activity assays for specific variants, CRISPR/Cas9 knock-in mouse with ultrastructural aortic phenotype

    PMID:26838787 PMID:27432961

    Open questions at the time
    • Penetrance modifiers in human TAAD families are unknown
    • Whether therapeutic LOX augmentation can prevent aneurysm progression is untested
  11. 2016 Medium

    Discovery that LOX directly binds the SNAI2 promoter and transcriptionally activates it revealed an unexpected nuclear/transcriptional function linking LOX to EMT beyond its extracellular enzymatic activity.

    Evidence ChIP and luciferase reporter assays, LOX knockdown in metastatic thyroid cancer mouse model

    PMID:27029493

    Open questions at the time
    • How secreted LOX accesses chromatin (nuclear import mechanism) is entirely uncharacterized
    • Whether SNAI2 transactivation requires LOX catalytic activity or is propeptide-mediated is unclear
  12. 2020 High

    Two studies deepened the mechanistic picture of LOX in disease: in TNBC, the HIF-1α/LOX/ITGA5/FN1/FAK-Src axis was shown to mediate chemoresistance (reversible by LOX or miR-142-3p), while in heart failure, Th17-derived IL-17 activates LOX via ERK/AP-1 and Treg-derived IL-10 suppresses it via JAK1/STAT3, regulating myocardial fibrosis.

    Evidence Multi-model TNBC study (organoids, xenografts, PDX, syngeneic) with BAPN and miR-142-3p; cardiac fibroblast co-culture with Th17/Treg and pathway inhibitors in HF rat model

    PMID:32415208 PMID:32649012

    Open questions at the time
    • Whether immune-cell regulation of LOX extends to tumor stroma is unknown
    • Clinical utility of LOX inhibition for chemoresistance reversal not tested in patients
  13. 2024 Medium

    LOX-mediated ECM stiffening was linked to mechanotransduction and cell death: in hypoxic-ischemic brain injury, LOX-driven collagen crosslinking increases tissue stiffness, activating the Piezo1 mechanosensor on neurons to trigger GPX4-dependent ferroptosis.

    Evidence In vitro/in vivo HIBD models, AFM stiffness measurements, pharmacological LOX inhibition with BAPN and traumatic acid, Piezo1 and ferroptosis assays

    PMID:39260063

    Open questions at the time
    • Whether LOX-Piezo1-ferroptosis axis operates in other ischemic tissues is unknown
    • Single-lab finding awaiting independent confirmation
    • Selectivity of traumatic acid as a LOX inhibitor in vivo is not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of full-length LOX (proenzyme or mature form) has not been determined, limiting understanding of substrate specificity, allosteric regulation by the propeptide, and rational drug design for LOX-targeted therapies in fibrosis, aneurysm, and cancer.
  • No crystal or cryo-EM structure of LOX
  • Mechanism of LOX nuclear import and transcriptional activity is unresolved
  • In vivo substrate hierarchy (elastin vs. collagen type specificity) not systematically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0140110 transcription regulator activity 1
Localization
GO:0005576 extracellular region 4 GO:0031012 extracellular matrix 4
Pathway
R-HSA-1474244 Extracellular matrix organization 6 R-HSA-162582 Signal Transduction 6 R-HSA-1643685 Disease 6
Partners
BMP1COL4A1ELNFBLN4FN1HIF1ASNAI2SRC

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Lysyl oxidase (LOX) catalyzes oxidation of lysine residues in elastin and collagen via a copper cofactor and a unique lysyl-tyrosylquinone (LTQ) carbonyl cofactor, initiating covalent crosslinkages that stabilize these fibrous ECM proteins. The catalytic activity has been shown to extend to basic globular proteins including histone H1. The propeptide domain suppresses catalytic activity. Biochemical characterization, cofactor identification, in vitro enzyme activity assays Journal of cellular biochemistry High 12577300
1996 Prolysyl oxidase (50 kDa proenzyme) is proteolytically processed to the mature active enzyme (~30 kDa) in the extracellular space by a secreted metalloproteinase activity; procollagen C-proteinase (BMP-1) was identified as the responsible enzyme, generating a mature N-terminus of Asp-Asp-Pro-Tyr. MMP-2 can also cleave the substrate but at a different site. Recombinant substrate cleavage assay, N-terminal sequencing, metalloproteinase inhibitor studies, synthetic peptide inhibition of processing in fibroblast cultures The Journal of biological chemistry High 8636136
2005 Cellular fibronectin (cFN) binds LOX with high affinity (Kd ~2.5 nM), comparable to LOX binding to tropoelastin (1.9 nM) and collagen I (5.2 nM), but much higher than plasma fibronectin. cFN acts as a scaffold for active LOX and is critical for proteolytic processing of the 45 kDa proenzyme to the 30 kDa active form; FN-null fibroblasts show dramatically decreased LOX processing and enzymatic activity. Yeast two-hybrid screen, GST pulldown, solid-phase binding assay (Kd measurement), immunofluorescence co-localization, LOX activity assay in FN-null cells The Journal of biological chemistry High 15843371
2005 Catalytically active LOX regulates breast cancer cell migration, motility, and cell-matrix adhesion formation through a hydrogen peroxide (H2O2)-mediated mechanism involving FAK and Src kinase activation. BAPN (irreversible LOX inhibitor) decreased migration, adhesion, and FAK/Src activation in invasive breast cancer cells; catalase treatment (H2O2 scavenger) abolished Src activation, linking LOX-generated H2O2 to downstream FAK/Src signaling. BAPN inhibitor treatment, MCF-7/LOX overexpression, migration/adhesion assays, Western blot for pFAK/pSrc, catalase H2O2 removal experiment Cancer research High 16357151
2009 Hypoxia-induced LOX secreted by breast tumor cells accumulates at premetastatic sites, crosslinks collagen IV in the basement membrane, and is essential for CD11b+ myeloid-derived bone marrow cell (BMDC) recruitment. CD11b+ cells adhere to crosslinked collagen IV and produce MMP-2, which cleaves collagen and enhances BMDC and tumor cell invasion. LOX inhibition (BAPN) prevents CD11b+ cell recruitment and metastatic growth. In vivo mouse metastasis model, LOX inhibition with BAPN, immunohistochemistry of human metastases, collagen IV crosslinking assays, CD11b+ cell depletion/rescue Cancer cell High 19111879
2009 LOX is upregulated by HIF-1 under hypoxia and, together with LOXL2 (also a direct HIF-1 target), is necessary and sufficient for hypoxic repression of E-cadherin, a hallmark of epithelial-to-mesenchymal transition (EMT). Activation of lysyl oxidases mediates cellular transformation and invasion downstream of HIF-1. HIF-1 transcriptional target validation (ChIP, reporter assays), LOX/LOXL2 knockdown, E-cadherin expression assays, cellular invasion assays, LOX overexpression rescue The Journal of biological chemistry High 20026874
2009 Fibulin-4 (FBLN4) specifically interacts with the propeptide domain of LOX and recruits LOX onto tropoelastin, facilitating elastin cross-linking. In FBLN4-null or reduced-expression mice (smooth muscle-specific Cre deletion), LOX fails to assemble onto tropoelastin, resulting in disorganized elastic laminae, arterial stiffness, and aortic aneurysm. In vitro protein interaction assays (FBLN4-LOX propeptide binding), conditional knockout mice, electron microscopy of elastic laminae, LOX localization assays Proceedings of the National Academy of Sciences of the United States of America High 19855011
2010 LKB1 negatively regulates LOX expression through the mTOR-HIF-1α signaling axis in lung cancer. LKB1 loss leads to upregulated LOX expression, excess collagen deposition, and enhanced cancer cell proliferation and invasiveness through activation of β1 integrin signaling. LOX inhibition (BAPN) dramatically alleviates lung cancer malignancy progression in LKB1-deficient tumors. LKB1 knockdown/overexpression, LOX inhibition with BAPN, mTOR-HIF-1α pathway analysis, β1 integrin signaling assays, mouse tumor models Proceedings of the National Academy of Sciences of the United States of America High 20956321
2011 LOX plays a critical role in colorectal cancer (CRC) proliferation and metastasis through activation of SRC kinase. LOX overexpression increased 3D proliferation and invasion; LOX knockdown reduced these phenotypes. LOX-mediated effects were inhibited by the SRC inhibitor dasatinib, establishing LOX→SRC as the mechanistic axis. LOX overexpression (SW480+LOX) and shRNA knockdown (SW620+shLOX), 3D proliferation/invasion assays, subcutaneous and intrasplenic mouse tumor models, dasatinib SRC inhibition Journal of the National Cancer Institute High 21282564
2011 TGFβ induces expression of LOX (and LOXL1-4) in human trabecular meshwork cells through both canonical Smad2/3/4 signaling and non-canonical JNK/AP-1 signaling pathways. BAPN inhibition of LOX activity blocked tropoelastin cross-linking, implicating LOX in TGFβ-mediated IOP elevation. RT-PCR, Western blot, TGFβ receptor inhibitors (LY364947, SB431542), Smad siRNA knockdown, JNK/AP-1 inhibitors (SP600125, SR11302), LOX activity assay with BAPN Investigative ophthalmology & visual science High 21546528
2012 In hypertensive patients with heart failure, collagen cross-linking (CCL) degree—but not total collagen amount—correlates with elevated filling pressures and chamber stiffness. LOX expression (assessed by Western blot in myocardial biopsies) correlates with CCL and insoluble collagen, supporting LOX as the mediator of pathological collagen stiffening. Human myocardial biopsy Western blot for LOX, colorimetric/enzymatic CCL assay, hemodynamic measurements (pulmonary capillary wedge pressure), histomorphometry Hypertension Medium 22824984
2003 LOX and four LOX-like proteins (LOXL1-4) each contain a copper-binding site, conserved lysyl and tyrosyl residues contributing to lysyl-tyrosylquinone (LTQ) cofactor formation, and a cytokine receptor-like (CRL) domain. LOX proteins differ in their N-terminal sequences, which confer individual functions; BMP-1 (procollagen C-proteinase) and possibly other enzymes process LOX proteins to generate multiple functional forms. Comparative sequence analysis, domain mapping, processing studies with BMP-1 Biochimica et biophysica acta Medium 12686136
2004 LOX is a tumor suppressor gene in human gastric cancers, inactivated by promoter methylation (27% of cases) and loss of heterozygosity (33%). Reintroduction of LOX into LOX-silenced gastric cancer cells (MKN28) reduced anchorage-dependent colony formation, anchorage-independent growth in soft agar, and tumor size in nude mice by ~74-81%. LOH analysis, bisulfite sequencing/methylation analysis, LOX re-expression in cancer cells, colony formation assays, xenograft tumor model Cancer research High 15374948
2009 LOX gene deficiency in mice leads to decreased osteoblast DNA synthesis, reduced mineral nodule formation, and decreased expression of osteoblastic differentiation markers (type I collagen, bone sialoprotein, Runx2/Cbfa1). Additionally, LOX deficiency causes significant downregulation of all four LOXL isoforms in bone tissue. Primary calvarial osteoblasts from Lox-/- mice, annexin-V apoptosis assay, DNA synthesis measurement, osteogenic differentiation markers by qPCR/Western blot Calcified tissue international Medium 19458888
2014 A loss-of-function polymorphism in the LOX propeptide domain (G473A; Arg158Gln in LOX-PP) profoundly impairs LOX-PP tumor suppressor function: the Gln variant cannot inhibit invasion or tumor formation of NF639 breast cancer cells (driven by HER2/neu→Ras), and shows attenuated opposition to pro-invasive LOX enzyme activity. LOX-PP Gln also failed to inhibit invasion by ER-negative cell lines. Xenograft tumor formation assay, invasion assay, comparison of wild-type vs. Gln158 LOX-PP, catalase/BAPN controls, case-control study in African American women Cancer research Medium 19654310
2015 LOX activity is required for ordered collagen fibrillogenesis in tendon: BAPN inhibition of LOX in human tenocyte tendon constructs blocked aldimine cross-link formation and led to mechanically weak constructs with structurally abnormal collagen fibrils (irregular profiles, widely dispersed diameters), independent of collagen content or collagen V/decorin/fibromodulin expression changes. BAPN treatment of human tenocyte tendon constructs, mechanical testing, electron microscopy of fibril ultrastructure, cross-link quantification, gene expression analysis The Journal of biological chemistry High 25979340
2015 LOX secreted by myofibers attenuates TGFβ signaling, an inhibitor of myofiber differentiation and promoter of muscle connective tissue (MCT) development. A TGFβ-LOX feedback loop between MCT and myofibers maintains the developmental balance between muscle components. LOX deletion in mice uncouples the balance between myofibers and MCT, leading to excess MCT and disorganized collagen. Conditional Lox knockout mice, TGFβ signaling assays, myofiber/MCT quantification, collagen organization analysis, rescue experiments Development High 25715398
2015 LOX inhibition (with BAPN) in KPC pancreatic cancer mice suppresses metastasis by inhibiting tumor cell migration and invasion. LOX inhibition synergizes with gemcitabine to prolong tumor-free survival, associated with stromal alterations including increased vasculature, decreased fibrillar collagen, and increased immune cell infiltration. KPC genetically engineered mouse model, BAPN treatment, gemcitabine combination, histological stromal analysis, migration/invasion assays, survival analysis EMBO molecular medicine High 26077591
2016 Rare heterozygous LOX mutations (including p.Ser280Arg, p.Ser348Arg, p.Trp42*, p.Gly202*, p.Thr248Ile, p.Gln267Pro) predispose to thoracic aortic aneurysms and dissections (TAAD). Variants affecting the conserved catalytic domain cause haploinsufficiency; expression of p.Ser280Arg and p.Ser348Arg results in significantly lower lysyl oxidase enzymatic activity compared to wild-type. Exome sequencing, Sanger sequencing, co-segregation analysis in families, lysyl oxidase activity assays for variant proteins Circulation research High 26838787
2016 A human LOX missense mutation (p.Met298Arg) causes TAAD; CRISPR/Cas9 knock-in mice heterozygous for this mutation display disorganized elastic lamellae in the aortic wall, while homozygous mice die perinatally from ascending aortic aneurysm and hemorrhage, consistent with insufficient LOX-mediated cross-linking of elastin and collagen. CRISPR/Cas9 knock-in mouse model, whole-genome sequencing, electron microscopy of aortic ultrastructure, co-segregation analysis Proceedings of the National Academy of Sciences of the United States of America High 27432961
2016 LOX binds to the SNAI2 promoter and transcriptionally activates SNAI2 (Slug) expression in cancer cells. LOX knockdown reduces SNAI2 expression in cancer cell lines and in a metastatic thyroid cancer mouse model; the LOX/SNAI2 axis regulates TIMP4 secretion, which plays a role in cancer progression. Chromatin immunoprecipitation (ChIP), promoter luciferase assay, LOX knockdown in cell lines and in vivo mouse model, protein array for MMPs/TIMPs Clinical cancer research Medium 27029493
2014 miR-30a directly targets LOX mRNA, decreasing LOX expression and inhibiting epithelial-mesenchymal transition, cellular invasion, migration, and metastatic capacity in anaplastic thyroid cancer. LOX was identified as a direct functional target of miR-30a regulating cancer progression. miR-30a overexpression/knockdown, LOX expression assays, EMT marker analysis, invasion/migration assays, in vivo metastasis model Cancer research Medium 25488748
2019 HIF2A (but not HIF1A) drives fibrotic ECM deposition in thyroid-associated orbitopathy (TAO) by inducing LOX expression. HIF2A or LOX inhibition (shRNA or small molecule antagonists) ameliorates fibrotic remodeling in 3D TAO orbital fibroblast organoids; conversely, constitutively active HIF2A in mouse orbital fibroblasts is sufficient to initiate LOX-dependent fibrotic remodeling. 3D organoid culture, shRNA knockdown, small molecule HIF2A/LOX inhibitors, constitutively active HIF2A overexpression, collagen deposition assays, IHC of human TAO tissue Endocrinology High 30388216
2020 Hypoxia-induced LOX reduces collagen cross-linking and fibronectin assembly in triple-negative breast cancer (TNBC), and its inhibition reduces ITGA5/FN1 expression, inhibits FAK/Src signaling, and re-sensitizes chemoresistant tumors to chemotherapy. LOX is regulated by HIF-1α, and its expression is suppressed by miR-142-3p which targets HIF1A, LOX, and ITGA5. RNA-seq transcriptomics of chemoresistant tumors, 3D cell culture, tumor organoids, chemoresistant xenografts, syngeneic tumors, PDX models, BAPN LOX inhibition, FAK/Src inhibitors, miR-142-3p re-expression Nature communications High 32415208
2020 Th17 cells promote LOX expression in cardiac fibroblasts via the IL-17/ERK1/2-AP-1 signaling pathway, while Tregs inhibit LOX expression via the IL-10/JAK1-STAT3 pathway. This Th17/Treg-regulated LOX expression drives collagen I/III and MMP-2/9 upregulation, contributing to myocardial fibrosis in heart failure. Cardiac fibroblast/Th17/Treg co-culture, Ang II stimulation, adoptive transfer in HF rat model, pathway inhibitor studies (ERK, AP-1, JAK1, STAT3) Acta physiologica Medium 32649012
2024 LOX increases collagen I/III deposition and promotes ECM remodeling/crosslinking in hypoxic-ischemic brain damage (HIBD), leading to increased tissue stiffness that activates the mechanosensitive ion channel Piezo1 in neurons, triggering ferroptosis in a GPX4-dependent manner. Pharmacological LOX inhibition (BAPN, and newly identified traumatic acid) prevented ECM stiffening, Piezo1 activation, and neuronal ferroptosis, improving learning and memory. In vitro and in vivo HIBD models, LOX activity/expression assays, AFM stiffness measurement, Piezo1 selective upregulation, ferroptosis assays (GPX4), pharmacological inhibition with BAPN and traumatic acid Redox biology Medium 39260063
2014 LOX secreted from vascular smooth muscle cells (VSMCs) is properly processed to its bioactive form; transgenic LOX overexpression in VSMCs (TgLOX mice) reduces VSMC proliferation, decreases Myh10 (SMC phenotypic switching marker), PCNA, and MCP-1, attenuates Akt and ERK1/2 mitogenic activation, and reduces neointimal thickening after carotid ligation. SM22α-driven LOX transgenic mice, VSMC isolation, proliferation assays, carotid ligation model, PCNA/MCP-1 immunostaining, Akt/ERK1/2 signaling assays Thrombosis and haemostasis Medium 24990180

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer cell 955 19111879
2003 Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. Journal of cellular biochemistry 757 12577300
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2013 LOX-1, OxLDL, and atherosclerosis. Mediators of inflammation 594 23935243
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
1998 Inducible gene targeting in mice using the Cre/lox system. Methods (San Diego, Calif.) 548 9608509
2004 Cre-lox-regulated conditional RNA interference from transgenes. Proceedings of the National Academy of Sciences of the United States of America 517 15240889
2011 Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways. Cell 507 21565611
2012 The rationale for targeting the LOX family in cancer. Nature reviews. Cancer 486 22810810
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2001 Lysyl oxidases: a novel multifunctional amine oxidase family. Progress in nucleic acid research and molecular biology 435 11642359
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2018 DNA Repair Network Analysis Reveals Shieldin as a Key Regulator of NHEJ and PARP Inhibitor Sensitivity. Cell 379 29656893
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2020 Targeting lysyl oxidase (LOX) overcomes chemotherapy resistance in triple negative breast cancer. Nature communications 284 32415208
2004 Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. Nature biotechnology 266 15146197
2019 Role of Ox-LDL and LOX-1 in Atherogenesis. Current medicinal chemistry 251 29737246
2011 Oxidized LDL, LOX-1 and atherosclerosis. Cardiovascular drugs and therapy 241 21947818
2012 LOX-1 in atherosclerosis: biological functions and pharmacological modifiers. Cellular and molecular life sciences : CMLS 240 23124189
2005 Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer research 240 16357151
2015 Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO molecular medicine 226 26077591
2009 The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1. The Journal of biological chemistry 216 20026874
2020 Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis. Hepatology (Baltimore, Md.) 213 32176358
2003 Structural and functional diversity of lysyl oxidase and the LOX-like proteins. Biochimica et biophysica acta 206 12686136
2019 LOX-1: Regulation, Signaling and Its Role in Atherosclerosis. Antioxidants (Basel, Switzerland) 205 31336709
2015 Cross-talk between LOX-1 and PCSK9 in vascular tissues. Cardiovascular research 204 26092101
2018 Detecting and Avoiding Problems When Using the Cre-lox System. Trends in genetics : TIG 195 29336844
2006 Cre-lox-based system for multiple gene deletions and selectable-marker removal in Lactobacillus plantarum. Applied and environmental microbiology 187 17142375
2006 Elastic fibres in health and disease. Expert reviews in molecular medicine 183 16893474
2020 PCSK9 and inflammation: role of shear stress, pro-inflammatory cytokines, and LOX-1. Cardiovascular research 180 31746997
2008 Cre/lox system and PCR-based genome engineering in Bacillus subtilis. Applied and environmental microbiology 179 18641148
2011 Transforming growth factor-beta induces extracellular matrix protein cross-linking lysyl oxidase (LOX) genes in human trabecular meshwork cells. Investigative ophthalmology & visual science 178 21546528
2016 LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circulation research 174 26838787
2011 The role of lysyl oxidase in SRC-dependent proliferation and metastasis of colorectal cancer. Journal of the National Cancer Institute 166 21282564
2012 Collagen cross-linking but not collagen amount associates with elevated filling pressures in hypertensive patients with stage C heart failure: potential role of lysyl oxidase. Hypertension (Dallas, Tex. : 1979) 165 22824984
1996 Metalloproteinase activity secreted by fibrogenic cells in the processing of prolysyl oxidase. Potential role of procollagen C-proteinase. The Journal of biological chemistry 165 8636146
2005 Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation. The Journal of biological chemistry 160 15843371
2010 LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proceedings of the National Academy of Sciences of the United States of America 159 20956321
2005 Abnormal deposition of collagen around hepatocytes in Wilson's disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. Journal of hepatology 156 16023247
2016 Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proceedings of the National Academy of Sciences of the United States of America 151 27432961
2001 LOX-1 supports adhesion of Gram-positive and Gram-negative bacteria. Journal of immunology (Baltimore, Md. : 1950) 145 11290792
2017 LOX-1 in Atherosclerosis and Myocardial Ischemia: Biology, Genetics, and Modulation. Journal of the American College of Cardiology 144 28571642
2004 Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. Cancer research 141 15374948
2015 Lysyl Oxidase Activity Is Required for Ordered Collagen Fibrillogenesis by Tendon Cells. The Journal of biological chemistry 139 25979340
2009 Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase. Proceedings of the National Academy of Sciences of the United States of America 135 19855011
2001 Activation-dependent surface expression of LOX-1 in human platelets. Biochemical and biophysical research communications 132 11263985
2011 The discovery of LOX-1, its ligands and clinical significance. Cardiovascular drugs and therapy 130 21805404
2007 Regulation of COX and LOX by curcumin. Advances in experimental medicine and biology 129 17569213
2014 LOX-1, mtDNA damage, and NLRP3 inflammasome activation in macrophages: implications in atherogenesis. Cardiovascular research 116 24776598
2018 LOX-1 receptor: A potential link in atherosclerosis and cancer. Life sciences 113 29462603
2012 Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies. Investigative ophthalmology & visual science 105 22661479
2020 Lysyl Oxidase (LOX): Functional Contributions to Signaling Pathways. Biomolecules 101 32708046
2009 Lox-1: the multifunctional receptor underlying cardiovascular dysfunction. Circulation journal : official journal of the Japanese Circulation Society 101 19801851
2001 Inhibition of LOX-1 by statins may relate to upregulation of eNOS. Biochemical and biophysical research communications 95 11735125
2003 Glucose enhances endothelial LOX-1 expression: role for LOX-1 in glucose-induced human monocyte adhesion to endothelium. Diabetes 91 12829655
2021 LOX-1 and cancer: an indissoluble liaison. Cancer gene therapy 89 33402733
2021 Cas12a-assisted precise targeted cloning using in vivo Cre-lox recombination. Nature communications 88 33608525
2006 Differential expression within the LOX gene family in ripening kiwifruit. Journal of experimental botany 87 17032731
2006 Reduction of isoforms of 15-lipoxygenase (15-LOX)-1 and 15-LOX-2 in human breast cancer. Prostaglandins, leukotrienes, and essential fatty acids 83 16556493
2019 HIF2A-LOX Pathway Promotes Fibrotic Tissue Remodeling in Thyroid-Associated Orbitopathy. Endocrinology 81 30388216
2006 LOX-1 scavenger receptor mediates calcium-dependent recognition of phosphatidylserine and apoptotic cells. The Biochemical journal 80 16146427
2014 Platelet 12-LOX is essential for FcγRIIa-mediated platelet activation. Blood 79 25100742
2000 TGF-beta1 downregulates CD36 and scavenger receptor A but upregulates LOX-1 in human macrophages. American journal of physiology. Heart and circulatory physiology 79 10749696
2018 Targeting LOX-1 in atherosclerosis and vasculopathy: current knowledge and future perspectives. Annals of the New York Academy of Sciences 76 30381837
2017 Human colorectal cancer progression correlates with LOX-induced ECM stiffening. International journal of biological sciences 72 29209148
2014 miR30a inhibits LOX expression and anaplastic thyroid cancer progression. Cancer research 71 25488748
2008 A combination of Lox-1 and Nox1 regulates TLR9-mediated foam cell formation. Cellular signalling 70 18817866
2007 The splice variant LOXIN inhibits LOX-1 receptor function through hetero-oligomerization. Journal of molecular and cellular cardiology 62 18191942
2019 Interplay Between LOX Enzymes and Integrins in the Tumor Microenvironment. Cancers 61 31130685
2016 Lysyl Oxidase (LOX) Transcriptionally Regulates SNAI2 Expression and TIMP4 Secretion in Human Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 58 27029493
2009 A loss-of-function polymorphism in the propeptide domain of the LOX gene and breast cancer. Cancer research 57 19654310
2010 Good planning and serendipity: exploiting the Cre/Lox system in the testis. Reproduction (Cambridge, England) 53 21084571
2009 Lysyl oxidase (lox) gene deficiency affects osteoblastic phenotype. Calcified tissue international 53 19458888
2019 Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure-Activity Relationships. Journal of medicinal chemistry 51 31070916
2015 Muscle composition is regulated by a Lox-TGFβ feedback loop. Development (Cambridge, England) 48 25715398
2012 LOX-1: a multiligand receptor at the crossroads of response to danger signals. Current opinion in lipidology 48 22777292
2016 Roles of LOX-1 in microvascular dysfunction. Microvascular research 47 26907636
2000 Oxidized-LDL and atherosclerosis. Role of LOX-1. Annals of the New York Academy of Sciences 47 10865829
2000 Inflammatory 5-LOX mRNA and protein are increased in brain of aging rats. Neurobiology of aging 47 11016533
2019 LOX-1 and atherosclerotic-related diseases. Clinica chimica acta; international journal of clinical chemistry 46 30639239
2014 FLP/FRT and Cre/lox recombination technology in C. elegans. Methods (San Diego, Calif.) 46 24874786
2014 LOX-1, oxidant stress, mtDNA damage, autophagy, and immune response in atherosclerosis. Canadian journal of physiology and pharmacology 46 24959993
2001 Identification of peptides that target the endothelial cell-specific LOX-1 receptor. Hypertension (Dallas, Tex. : 1979) 45 11230317
2015 Molecular mechanism of statin-mediated LOX-1 inhibition. Cell cycle (Georgetown, Tex.) 44 25950192
2020 Th17/Treg imbalance modulates rat myocardial fibrosis and heart failure by regulating LOX expression. Acta physiologica (Oxford, England) 43 32649012
2016 LOX-1 and TLR4 affect each other and regulate the generation of ROS in A. fumigatus keratitis. International immunopharmacology 43 27694040
2022 Dysregulation of interaction between LOXhigh fibroblast and smooth muscle cells contributes to the pathogenesis of aortic dissection. Theranostics 42 34976220
2018 Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited. Bioorganic & medicinal chemistry letters 42 30098867
2020 Fisetin ameliorates atherosclerosis by regulating PCSK9 and LOX-1 in apoE-/- mice. Experimental and therapeutic medicine 41 33262811
2011 LOX-1 and angiotensin receptors, and their interplay. Cardiovascular drugs and therapy 41 21861069
2018 Silibinin Inhibits NSCLC Metastasis by Targeting the EGFR/LOX Pathway. Frontiers in pharmacology 39 29472856
2018 MicroRNA-98 regulates foam cell formation and lipid accumulation through repression of LOX-1. Redox biology 39 29549823
2017 Xanthine Oxidase Induces Foam Cell Formation through LOX-1 and NLRP3 Activation. Cardiovascular drugs and therapy 39 28084571
2023 Single-cell analysis reveals lysyl oxidase (Lox)+ fibroblast subset involved in cardiac fibrosis of diabetic mice. Journal of advanced research 37 36706988
2017 LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and Cancer-Targeted Therapies. International journal of molecular sciences 35 28146073
2021 Lipoxygenase (LOX) Pathway: A Promising Target to Combat Cancer. Current pharmaceutical design 34 33388012
2019 Upregulated LOX-1 Receptor: Key Player of the Pathogenesis of Atherosclerosis. Current atherosclerosis reports 34 31350594
2013 Oxidized LDL and LOX-1 in experimental sepsis. Mediators of inflammation 31 24000272
2011 LOX-1 and obesity. Cardiovascular drugs and therapy 31 21881850
2012 The LOX-1 Scavenger Receptor and Its Implications in the Treatment of Vascular Disease. Cardiology research and practice 30 22454776
2019 Pro-oncogenic action of LOX-1 and its splice variant LOX-1Δ4 in breast cancer phenotypes. Cell death & disease 28 30718451
2014 Lysyl oxidase (LOX) in vascular remodelling. Insight from a new animal model. Thrombosis and haemostasis 28 24990180
2007 Expression of 5-lipoxygenase (5-LOX) in T lymphocytes. Immunology 28 17484769
2014 Berberine combined with atorvastatin downregulates LOX‑1 expression through the ET‑1 receptor in monocyte/macrophages. International journal of molecular medicine 27 24756769
2011 Novel concepts in the genesis of hypertension: role of LOX-1. Cardiovascular drugs and therapy 26 21912849
2020 HRD1 prevents atherosclerosis-mediated endothelial cell apoptosis by promoting LOX-1 degradation. Cell cycle (Georgetown, Tex.) 25 32308114
2015 Membrane Cholesterol Modulates LOX-1 Shedding in Endothelial Cells. PloS one 25 26495844
2012 The new role of LOX-1 in hypertension induced neuronal apoptosis. Biochemical and biophysical research communications 25 22885180
2018 Toll-like receptor 2 activation primes and upregulates osteoclastogenesis via lox-1. Lipids in health and disease 24 29859535
2011 Angiogenesis is a link between atherosclerosis and tumorigenesis: role of LOX-1. Cardiovascular drugs and therapy 24 21968594
2010 [LOX-1 receptor as a novel target in endothelial dysfunction and atherosclerosis]. Deutsche medizinische Wochenschrift (1946) 24 20146162
2013 Concentration polarization of ox-LDL activates autophagy and apoptosis via regulating LOX-1 expression. Scientific reports 23 23807658
2012 Plant 9-lox oxylipin metabolism in response to arbuscular mycorrhiza. Plant signaling & behavior 23 23073021
2022 Cre/lox regulated conditional rescue and inactivation with zebrafish UFlip alleles generated by CRISPR-Cas9 targeted integration. eLife 22 35713402
2021 Effects of Apigenin on the Expression of LOX-1, Bcl-2, and Bax in Hyperlipidemia Rats. Chemistry & biodiversity 22 34118114
1994 TKO'ed: lox, stock and barrel. BioEssays : news and reviews in molecular, cellular and developmental biology 22 7840765
2021 Urine LOX-1 and Volatilome as Promising Tools towards the Early Detection of Renal Cancer. Cancers 21 34439368
2019 Celastrol ameliorates Aspergillus fumigatus keratitis via inhibiting LOX-1. International immunopharmacology 21 30798158
2015 The Role of LOX and LOXL2 in the Pathogenesis of an Experimental Model of Choroidal Neovascularization. Investigative ophthalmology & visual science 21 26258612
2015 The human rs1050286 polymorphism alters LOX-1 expression through modifying miR-24 binding. Journal of cellular and molecular medicine 21 26542080
2013 TAILOR: transgene activation and inactivation using lox and rox in zebrafish. PloS one 21 24391998
2024 LOX-1 in Cardiovascular Disease: A Comprehensive Molecular and Clinical Review. International journal of molecular sciences 20 38791315
2022 Identification of the LOX Gene Family in Peanut and Functional Characterization of AhLOX29 in Drought Tolerance. Frontiers in plant science 20 35356112
2018 Overexpression of Lox in triple-negative breast cancer. Annals of diagnostic pathology 20 29661738
2024 LOX-mediated ECM mechanical stress induces Piezo1 activation in hypoxic-ischemic brain damage and identification of novel inhibitor of LOX. Redox biology 19 39260063
2011 LOX-1: a critical player in the genesis and progression of myocardial ischemia. Cardiovascular drugs and therapy 19 21847544
2006 Lysyl oxidase (LOX) and hypoxia-induced metastases. Cancer biology & therapy 19 16969095