Affinage

LCN2

Neutrophil gelatinase-associated lipocalin · UniProt P80188

Length
198 aa
Mass
22.6 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LCN2 (NGAL/24p3) is a secreted lipocalin that binds small hydrophobic ligands—fatty acids, retinoids, cholesteryl esters, and the formyl peptide fMLP—within a beta-barrel pocket and acts as a bidirectional regulator of cellular iron, apoptosis, and inflammation (PMID:9894844, PMID:9266486). It was first isolated biochemically as a 25-kDa protein physically associated with neutrophil gelatinase (MMP-9) in a stable heterodimeric complex (PMID:7683678). Its central mechanism is iron-state-dependent signaling through the cell-surface receptor SLC22A17 (24p3R): iron-loaded LCN2 delivers iron, whereas iron-free LCN2 depletes intracellular iron, induces Bim, and triggers apoptosis (PMID:16377569), a pathway confirmed in vivo by attenuated Bim induction and apoptotic resistance in 24p3-null hematopoietic cells (PMID:21507940). Through 24p3R, LCN2 also mediates receptor-dependent endocytosis and transcytosis of protein-metal complexes in distal nephron and intestinal epithelia, where ligand uptake drives NF-κB/TGF-β1 proinflammatory and profibrotic signaling (PMID:22084236, PMID:23940770, PMID:23884139). In the kidney LCN2 additionally promotes CamK2β-dependent phosphorylation of the sodium-chloride cotransporter NCC to modulate sodium balance (PMID:37377014). LCN2 transcription is directly controlled by Foxo3a (repressed by IL-3/PI3K/Akt) (PMID:19056725), Stat5 downstream of BCR-ABL (PMID:19229297), glucocorticoid receptor (PMID:8666241), TLR-4/NF-κB signaling (PMID:17490638), and H3K9 β-hydroxybutyrylation at its promoter (PMID:40022118). In cancer, LCN2 binds EGFR to sustain its recycling and MEK-ERK activation (PMID:36899380), forms ternary complexes with LOXL2 and MMP9 to drive ECM degradation and invasion (PMID:37753805), and confers ferroptosis resistance by sequestering iron downstream of LIFR loss or MafG/MYH9 activation (PMID:34921145, PMID:38871948). Secreted from reactive astrocytes via NOX-NF-κB-dependent exosomal release, LCN2 drives neuronal death and neuroinflammation (PMID:35440572, PMID:36781380), and its abundance is constrained post-translationally by FBXO2-mediated K27-linked polyubiquitination and degradation (PMID:40791152).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1993 High

    Established LCN2's first defined biochemical context—physical partnership with MMP-9—identifying it as a secreted neutrophil lipocalin rather than an orphan protein.

    Evidence Immunoprecipitation, protein purification, and N-terminal sequencing of the 135-kDa complex from neutrophil exocytosed material

    PMID:7683678

    Open questions at the time
    • Functional consequence of the LCN2-MMP9 complex not addressed
    • Ligand-binding activity not yet demonstrated
  2. 1998 Medium

    Defined LCN2 as a genuine ligand carrier by showing direct binding of fatty acids, retinoids, and the formyl peptide fMLP in its beta-barrel pocket, grounding the predicted lipocalin function in experiment.

    Evidence Circular dichroism, fluorescence quenching, and radiolabeled-ligand binding assays with purified mouse 24p3

    PMID:9266486 PMID:9894844

    Open questions at the time
    • No mutagenesis confirming the binding-site residues
    • Physiological relevance of each ligand not established
    • Single-lab in vitro affinities only
  3. 2005 High

    Resolved how a secreted lipocalin can act on cells by cloning the receptor SLC22A17 and demonstrating iron-state-dependent bidirectional signaling—iron delivery versus iron withdrawal with Bim-driven apoptosis—and linked this to BCR-ABL leukemia biology.

    Evidence Receptor cloning, ectopic expression, iron uptake and apoptosis assays, Bim analysis, BCR-ABL/imatinib cell experiments

    PMID:16377569

    Open questions at the time
    • Structural basis of iron-loaded versus iron-free receptor engagement unresolved
    • How receptor distinguishes loading state mechanistically unclear
  4. 2009 High

    Mapped the transcriptional control circuitry of LCN2, showing it is a direct target of Foxo3a (repressed by PI3K/Akt), Stat5, glucocorticoid receptor, and TLR-4/NF-κB, explaining its inducibility by stress, hormones, oncogenes, and infection.

    Evidence Promoter binding assays, luciferase reporters with deletion mapping, pathway inhibitors, phospho-resistant mutants, and TLR-4 mutant mice across multiple studies

    PMID:17490638 PMID:19056725 PMID:19229297 PMID:8666241

    Open questions at the time
    • Combinatorial logic between these inputs not integrated
    • Cell-type-specific dominance of each factor unclear
  5. 2011 High

    Confirmed the iron/apoptosis axis physiologically using 24p3-null mice, demonstrating attenuated Bim induction and apoptotic defects across multiple hematopoietic lineages.

    Evidence Genetic knockout mice on two backgrounds, flow cytometry apoptosis assays, Bim expression analysis

    PMID:21507940

    Open questions at the time
    • Whether all phenotypes are receptor-dependent not fully dissected
    • Iron-flux measurements in vivo not provided
  6. 2013 High

    Extended receptor function beyond iron to epithelial cargo handling, showing 24p3R mediates apical endocytosis and transcytosis of protein-metal complexes in kidney and gut and activates NF-κB/TGF-β1 profibrotic signaling.

    Evidence Fluorescent ligand internalization, Transwell transcytosis, microscale thermophoresis, siRNA, and NF-κB reporter assays in epithelial cells and ex vivo ducts

    PMID:22084236 PMID:23884139 PMID:23940770

    Open questions at the time
    • Relative in vivo contribution of transcytosis versus iron signaling unclear
    • Receptor trafficking itinerary not fully mapped
  7. 2013 High

    Revealed an iron-independent immune role: LCN2 supports neutrophil cytoskeletal reorganization, chemotaxis, and phagocytosis, distinguishing this from siderophore sequestration.

    Evidence 24p3-null mice, infection models, chemotaxis/phagocytosis assays, transcriptome and microRNA analysis

    PMID:23543755

    Open questions at the time
    • Molecular target linking LCN2 to cytoskeletal gene regulation unknown
    • Whether this requires receptor signaling unresolved
  8. 2018 High

    Identified a renal physiological role for LCN2 in sodium handling via CamK2β-dependent NCC phosphorylation, broadening its function from injury marker to electrolyte regulator.

    Evidence Lcn2-KO mice, recombinant protein reconstitution, ex vivo kidney slices with CamK2β inhibition, NCC phospho-immunoblotting

    PMID:37377014

    Open questions at the time
    • Receptor mediating the NCC effect not defined
    • Link between iron biology and CamK2β signaling absent
  9. 2021 High

    Connected LCN2's iron sequestration to ferroptosis control in cancer, showing LIFR loss drives NF-κB-dependent LCN2 upregulation that depletes iron and confers ferroptosis resistance, with therapeutic neutralization restoring sensitivity.

    Evidence Hepatocyte-specific Lifr-KO mice, iron measurements, ferroptosis drug assays, LCN2-neutralizing antibody in PDX models

    PMID:34921145

    Open questions at the time
    • Whether receptor signaling or extracellular iron chelation dominates unclear
    • Generality across tumor types not established here
  10. 2024 High

    Detailed LCN2's pro-tumor signaling repertoire, showing it binds EGFR to sustain recycling and MEK-ERK output, forms invasion-promoting LOXL2/MMP9 complexes, and is transcriptionally driven by a MafG/MYH9 complex to maintain ferroptosis resistance.

    Evidence Mass spectrometry, Co-IP, EGFR recycling assays, ECM degradation assays, ChIP with MARE-motif mutagenesis, and in vivo tumor/fibrosis models

    PMID:36899380 PMID:37753805 PMID:38871948

    Open questions at the time
    • Stoichiometry and structural basis of LCN2-EGFR and ternary complexes unresolved
    • Whether these are receptor-dependent or receptor-independent functions unclear
  11. 2023 High

    Defined how LCN2 secretion and abundance are post-transcriptionally and post-translationally gated—NF-κB- and signal-peptide-dependent astrocyte secretion, exosomal NOX-NF-κB release, autophagic/lysosomal degradation, and FBXO2-mediated K27-ubiquitination—linking LCN2 levels to neuronal death and ferroptosis.

    Evidence Pharmacological proteasome/mTOR inhibition, signal-peptide mutants, exosome isolation, conditional NHE1 KO, Co-IP, and ubiquitination assays with neuronal viability endpoints

    PMID:35440572 PMID:36781380 PMID:40791152

    Open questions at the time
    • How distinct secretory routes are selected in different cell types unclear
    • FBXO2 result is single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LCN2's distinct activities—iron carriage, receptor signaling, ECM/EGFR partnerships, and epithelial transcytosis—are coordinated within a single cell and how iron-loading state is sensed at the receptor remain unresolved.
  • No structural model of iron-loaded versus iron-free LCN2-receptor engagement
  • Integration of receptor-dependent and receptor-independent functions not established
  • Whether MMP9/LOXL2/EGFR complexes require iron status unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0008289 lipid binding 2 GO:0140104 molecular carrier activity 2
Localization
GO:0005576 extracellular region 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
EGFRFBXO2LOXL2MMP9SLC22A17
Complex memberships
LCN2-LOXL2-MMP9 ternary complexLCN2-MMP9 heterodimer

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 NGAL (LCN2) was identified as a 25-kDa protein physically associated with the 92-kDa human neutrophil gelatinase (MMP-9), forming a 135-kDa heterodimeric complex; this association was demonstrated by immunoprecipitation and immunoblotting, and the protein was purified from neutrophil exocytosed material and sequenced as a new member of the lipocalin family. Immunoprecipitation, immunoblotting, protein purification, N-terminal sequencing, N-glycanase treatment The Journal of biological chemistry High 7683678
2005 LCN2 (24p3) mediates apoptosis or iron uptake depending on its iron-loading state through a cloned cell-surface receptor (24p3R/SLC22A17): iron-loaded LCN2 increases intracellular iron without promoting apoptosis, while iron-free LCN2 decreases intracellular iron, induces Bim expression, and triggers apoptosis. BCR-ABL activates 24p3 expression and represses 24p3R expression, rendering BCR-ABL+ cells resistant to secreted LCN2-induced apoptosis. Receptor cloning, ectopic expression, iron uptake assays, apoptosis assays, Bim expression analysis, BCR-ABL/imatinib cell line experiments Cell High 16377569
1991 Mouse 24p3 protein (LCN2 ortholog) was identified as a member of the lipocalin family based on conserved sequence motifs, predicting a ligand-binding function for small hydrophobic molecules. Computational sequence analysis using conserved lipocalin motifs Biochemical and biophysical research communications Low 1834059
1998 Mouse 24p3 protein (LCN2) binds hydrophobic ligands including fatty acids (oleic acid), retinol, retinoic acid, and cholesteryl oleate within a beta-barrel hydrophobic pocket, with association constants in the 10^5–10^6 M^-1 range; Trp-31 and/or Trp-81 are located at or near the binding site. Circular dichroism spectroscopy, intrinsic fluorescence quenching, fluorescence binding assay with [3H]-retinol and [3H]-retinoic acid, acrylamide/CsCl/KI quenching The journal of peptide research Medium 9894844
1997 Purified mouse 24p3 (LCN2) protein forms a complex with the formyl peptide fMLP (formyl-Met-Leu-Phe), as demonstrated by fluorescence quenching, with an association constant of ~4.8 × 10^5 M^-1; the N-terminus is blocked by pyroglutamate resulting from post-translational cleavage at Ala-Gln. Fluorescence spectroscopy, protein purification, N-terminal sequencing The journal of peptide research Medium 9266486
1989 SV40 large T-antigen induces a post-transcriptional increase in 24p3 (LCN2) mRNA levels, consistent with increased pre-mRNA processing efficiency (possibly splicing), rather than transcriptional activation or mRNA stabilization. Northern blotting, cDNA library construction, infection with wt vs. T-antigen-deficient SV40, cycloheximide and actinomycin D controls Oncogene Medium 2542864
1996 Dexamethasone (glucocorticoid) directly induces mouse 24p3 (LCN2) transcription via glucocorticoid-responsive elements (GREs) in its promoter, with a 43-bp region required for dexamethasone responsiveness; retinoic acid similarly induces expression. The induction is amplified by an autocrine mechanism. CAT reporter gene assay, promoter deletion analysis, cycloheximide treatment (absence of new protein synthesis requirement), Northern blotting, primer extension for TSS Gene High 8666241
2009 BCR-ABL upregulates 24p3 (LCN2) expression via the JAK/STAT pathway, specifically through Stat5 binding to the 24p3 promoter. BCR-ABL represses 24p3R expression by inducing a switch from Runx3 (activator) to Runx1 (repressor) binding via a Ras signaling pathway. Repression of 24p3R by BCR-ABL is critical for imatinib-induced killing of BCR-ABL+ cells. Promoter binding assays (ChIP/EMSA), cell signaling pathway inhibition, luciferase reporter assays, overexpression/knockdown of pathway components The EMBO journal High 19229297
2008 24p3 (LCN2) is a direct transcriptional target of Foxo3a, and IL-3 represses 24p3 expression through the PI3K/Akt pathway (but not MAPK pathway): Foxo3a directly binds the 24p3 promoter and activates it; constitutively active Akt blocks Foxo3a-dependent 24p3 induction and apoptosis. Promoter binding assay (Foxo3a binding to 24p3 promoter), luciferase reporter assay, constitutively active Akt overexpression, PI3K/MAPK inhibitors, Foxo3a 3A (Akt-non-phosphorylatable) mutant The Journal of biological chemistry High 19056725
2007 LCN2 (24p3) upregulation in lung and liver during acute endotoxemia is dependent on functional TLR-4 signaling, and is associated with NF-κB and C/EBP activation in macrophages and type II alveolar epithelial cells, respectively. RT-PCR, Western blot, immunohistochemistry, C3H/HeJ TLR-4 mutant mice comparison, NF-κB and C/EBP nuclear binding activity assays Experimental and molecular pathology Medium 17490638
2011 24p3R (SLC22A17), the LCN2 receptor, is expressed in apical membranes of distal tubules and collecting ducts (not proximal tubule) of the rodent kidney and mediates receptor-mediated endocytosis of protein-metal complexes including metallothionein, transferrin, albumin, and cadmium-metallothionein; uptake of cadmium-MT via 24p3R causes cell death. Immunostaining of kidney tissue, cell line expression in CHO and distal tubule cells, fluorescence-coupled protein internalization assays, microscale thermophoresis (EC50 determination), siRNA knockdown, picomolar-range competition with 24p3 The Journal of biological chemistry High 22084236
2013 The 24p3R receptor mediates albumin endocytosis in collecting duct cells and activates NF-κB and TGF-β1 signaling pathways in response to albuminuria, contributing to proinflammatory and profibrotic responses in the distal nephron. FITC-albumin uptake assay, NF-κB luciferase reporter assay, nuclear translocation immunofluorescence, Snail/vimentin profibrotic markers, siRNA knockdown of 24p3R, isolated cortical collecting ducts from PAN nephrotic rats American journal of physiology. Renal physiology Medium 23884139
2013 24p3/LCN2 receptor (24p3R/SLC22A17) is expressed apically in ileum and colon epithelia and mediates high-affinity (EC50 ~18.6 nM) apical internalization and transcytosis of phytochelatin, metallothionein, and transferrin; apical uptake of these ligands is blocked by picomolar concentrations of NGAL. Immunofluorescence, RT-PCR, immunoblotting of plasma membrane fractions, fluorescent ligand internalization assays, Transwell transcytosis assays, microscale thermophoresis binding affinity measurement PloS one High 23940770
2007 LCN2 (24p3) promotes intestinal mucosal cell migration (restitution) 3- to 4-fold without affecting proliferation; both wild-type Cys98-LCN2 and mutant Ala98-LCN2 have similar pro-migratory activity, suggesting the Cys98 residue is not required for this function. Subcutaneous LCN2 reduces gastric damage in indomethacin-treated rats by ~60%. [3H]-thymidine proliferation assay, cell-wounding migration (restitution) assay in HT29 and HCT116 cells, rat gastric damage model with recombinant proteins Gastroenterology Medium 16952550
2003 24p3 (LCN2) expression is induced by MK886 (a FLAP inhibitor) in FL5.12 prolymphoid cells and contributes mechanistically to apoptosis: antisense knockdown of 24p3 reduces apoptosis in parallel with protein levels; apoptosis proceeds through caspase-3 activation and is blocked by Bcl-2/Bcl-xL overexpression. RT-PCR, Western blot, antisense cDNA stable transfection, caspase-3 cleavage assay, Bcl-2/Bcl-xL overexpression, PPARα/γ agonist modulation The Biochemical journal Medium 12614196
2004 Overexpression of 24p3 (LCN2) in HC11 mammary epithelial cells increases apoptosis 3- to 4-fold; 24p3 expression is induced during mammary gland involution and by dexamethasone, and expression is localized to secretory epithelial cells of alveoli. Northern blot, RNA in situ hybridization, transient transfection with 24p3 expression construct, apoptosis quantification Molecules and cells Medium 15055523
2011 In vivo studies with 24p3 (LCN2) null mice reveal apoptotic defects in mature hematopoietic cells (neutrophils, mast cells, thymocytes, erythroid cells); Bim induction in response to apoptotic stimuli is attenuated in 24p3-/- cells, explaining their resistance to apoptosis. Genetic knockout (24p3-/- mice on C57BL/6 and 129/SVE backgrounds), flow cytometry for apoptosis, competitive repopulation assay, Bim expression analysis, dexamethasone-induced thymocyte apoptosis The Journal of biological chemistry High 21507940
2013 LCN2-deficient (24p3-/-) neutrophils fail to extravasate to infection sites and are defective in chemotaxis and bacterial phagocytosis; transcriptome analysis shows selective suppression of cytoskeletal reorganization genes and increased microRNAs targeting upstream regulators of cytoskeletal proteins in 24p3-/- neutrophils. Susceptibility of 24p3-/- mice to Listeria, Candida, and Staphylococcus is due to impaired neutrophil function rather than iron/siderophore sequestration. Genetic knockout (24p3-/- mice), in vivo infection models (Listeria, Candida, S. aureus), chemotaxis assay, phagocytosis assay, transcriptome analysis, microRNA analysis Journal of immunology High 23543755
2007 Lipocalin 24p3 (LCN2) regulates iron transport bidirectionally through its receptor: iron-loaded 24p3 is internalized to deliver iron, while iron-free 24p3 withdraws iron from cells via a reverse mechanism. Wnt pathway activation decreases 24p3 expression independently of intracellular iron levels. Cellular iron level measurements, 24p3 expression analysis in Wnt-activated vs. control cells, iron addition/withdrawal experiments, 24p3R transcript splicing analysis Cancer genetics and cytogenetics Low 17350462
2014 LCN2 regulates hepatic lipid droplet formation by controlling expression of the lipid droplet coat protein PLIN5 (OXPAT): LCN2-deficient mice fed MCD diet accumulate more hepatic lipids with reduced basal PLIN5 expression; restoration of LCN2 in Lcn2-/- primary hepatocytes by transfection or adenoviral infection restores PLIN5 expression and normal lipid droplet formation. Lcn2-/- knockout mouse model, MCD diet feeding, adenoviral LCN2 re-expression in primary hepatocytes, transfection, immunoblotting, lipid droplet imaging Biochimica et biophysica acta High 25086218
2021 Loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of LCN2, which depletes iron and confers resistance to ferroptosis inducers in hepatocellular carcinoma. LCN2-neutralizing antibody enhances ferroptosis-inducing and anticancer effects of sorafenib on HCC PDX tumors. Hepatocyte-specific and inducible Lifr-knockout mice, NF-κB signaling analysis, iron level measurements, ferroptosis drug sensitivity assays, LCN2-neutralizing antibody in PDX tumor models Nature communications High 34921145
2023 Proteasome inhibition suppresses LCN2 secretion from reactive astrocytes by stabilizing IκBα and thereby blocking NF-κB activation. Autophagic flux activation via mTOR inhibition reduces intracellular LCN2 through pre-secretory lysosomal degradation. The N-terminal signal peptide of LCN2 is critical for both its secretion and its autophagic degradation. LPS-stimulated primary astrocyte cultures, proteasome inhibitor (bortezomib), mTOR inhibitor (rapamycin), IκBα immunoblotting, LCN2 secretion ELISA, signal peptide deletion constructs, neuronal viability assay with astrocyte-conditioned medium Autophagy High 36781380
2022 Reactive astrocyte LCN2 expression and secretion is regulated through NADPH oxidase (NOX)-NF-κB signaling: inhibition of NHE1 activity attenuates NOX signaling, reduces LCN2+ exosome secretion, and decreases LCN2-mediated neuronal apoptosis and neurite degeneration. LCN2 is secreted from reactive astrocytes in exosomes and induces neuronal cell death. Astrocyte-specific NHE1 knockout mice (Gfap-CreER+/-;Nhe1f/f), in vitro ischemia in astrocyte cultures, LCN2 exosome isolation, neuronal death assay, HOE642 NHE1 inhibitor, NOX inhibitor, immunostaining Cell death & disease High 35440572
2022 LCN2 mediates psoriatic skin inflammation through the SREBP2-NLRC4 axis: LCN2 binds its receptor 24p3R on keratinocytes, activates cholesterol biosynthesis signaling via SREBP2, which binds the NLRC4 promoter and induces its expression and downstream proinflammatory factors (IL-1β, IL-23, CXCL1, CXCL10). Silencing 24p3R or SREBP2 attenuates psoriasis-like inflammation in vivo. 24p3R/slc22a17 silencing in imiquimod-induced psoriasis mouse model, SREBP2 inhibition in vivo, LCN2 treatment of primary keratinocytes, SREBP2 promoter binding to NLRC4 (ChIP or reporter), siRNA experiments The Journal of investigative dermatology High 35120997
2019 CD4+ T cell-derived NGAL (LCN2) modifies ischemic AKI outcome: NGAL KO mice have worse renal outcomes than WT; adoptive transfer of NGAL-deficient CD4+ T cells leads to worse renal function; NGAL-deficient CD4+ T cells express higher IFN-γ mRNA under ischemic conditions; Lcn2 expression is induced in Th17, Th1, and Th2 differentiation. NGAL knockout mice, adoptive transfer of NGAL-deficient CD4+ T cells into CD4 KO or WT mice, renal function readouts, qRT-PCR, ELISA, in vitro ischemia/reperfusion simulation, CD4+ T cell differentiation assays Journal of immunology High 31889023
2018 NGAL/LCN2 modulates renal sodium balance by promoting phosphorylation of the sodium-chloride cotransporter (NCC) in the kidney cortex via CamK2β activation: recombinant LCN2 injection in Lcn2 KO mice induces NCC phosphorylation and decreases urinary Na excretion; CamK2β inhibition blocks LCN2-induced NCC phosphorylation in ex vivo kidney slices. Lcn2-knockout mice, recombinant murine lcn2 injection, ex vivo kidney slice experiments, NCC phosphorylation immunoblotting, CamK2β inhibitor, urinary Na excretion measurement, blood pressure telemetry Hypertension High 37377014
2024 MafG physically interacts with MYH9 (non-muscle myosin IIa) to transcriptionally activate LCN2 expression; this MafG/MYH9-LCN2 axis promotes hepatic stellate cell resistance to ferroptosis and drives liver fibrosis. Site-directed mutations of the MARE motif block MafG binding to the LCN2 promoter. Re-expression of LCN2 in MafG-knockdown HSCs restores ferroptosis resistance. Co-immunoprecipitation (MafG-MYH9 interaction), ChIP (MafG binding to LCN2 promoter), MARE motif mutagenesis, MafG knockdown/overexpression, LCN2 re-expression, ferroptosis assays, AAV-6 in vivo delivery, BDL mouse model Cell death and differentiation High 38871948
2023 LCN2 binds EGFR and promotes EGFR recycling, thereby sustaining EGFR phosphorylation and downstream MEK-ERK cascade activation in oral squamous cell carcinoma; LCN2 inhibition reduces EGFR recycling and downstream signaling, suppressing OSCC proliferation and metastasis. Mass spectrometry, Co-IP/pulldown (LCN2-EGFR interaction), EGFR recycling assay, immunofluorescence, immunoblotting (EGFR phosphorylation, MEK-ERK), siRNA knockdown, xenograft and PDX in vivo models with siLCN2 nanoparticle delivery Journal of experimental & clinical cancer research High 36899380
2023 LCN2 forms a ternary complex with LOXL2 and MMP9 (LCN2-LOXL2 and LCN2-MMP9 interactions occur both intracellularly and extracellularly; LOXL2-MMP9 only intracellularly); this complex promotes ESCC cell migration/invasion, fibronectin/Matrigel degradation, filopodia formation, microfilament rearrangement via profilin-1 upregulation, SPOCK1 expression, and FAK/AKT/GSK3β signaling. Protein-protein interaction assays (Co-IP, subcellular fractionation), invasion/migration assays, ECM degradation assays, filopodia imaging, profilin-1 Western blot, FAK/AKT/GSK3β phosphorylation analysis, in vivo tumor models Molecular oncology Medium 37753805
2024 LCN2 binds its receptor 24p3R via autocrine signaling to directly inhibit JNK phosphorylation, thereby suppressing the JNK/c-Jun pathway and downstream SPARC expression, which impairs gastric cancer proliferation and metastasis. Transcriptome sequencing, LCN2 overexpression/knockdown in vitro and in vivo, 24p3R binding/signaling assays, JNK phosphorylation immunoblotting, c-Jun ChIP on SPARC promoter, clinical correlation analyses Cell death & disease Medium 39424639
2018 In inner medullary collecting duct cells, hyperosmolarity/hypertonicity upregulates LCN2 receptor (SLC22A17) expression ~4-fold and decreases LCN2 expression/secretion via Wnt/β-catenin activation; β-catenin silencing reverses these effects. Conversely, LPS-mediated TLR-4 activation and normosmolarity downregulate the receptor and upregulate LCN2. Primary rat IMCD and mIMCD3 cell cultures, hyperosmotic media, qPCR, immunoblotting, flow cytometry, immunofluorescence, RNAi (β-catenin), LPS treatment, cell viability assays Cell communication and signaling Medium 30404645
2025 FBXO2 binds LCN2 via its FBA domain and promotes K27-linked polyubiquitination of LCN2, driving its proteasomal degradation; this suppresses LCN2-induced ferroptosis in nucleus pulposus cells. LCN2 silencing in FBXO2-deficient mice partially restores disc integrity. Proteomics, Co-IP (FBXO2-LCN2 binding), ubiquitination assays (K27-linked polyubiquitination), proteasome inhibitor rescue, FBXO2 overexpression/knockdown, LCN2 silencing in FBXO2-KO mice, in vivo AAV9-mediated overexpression Advanced science Medium 40791152
2025 BDH1 overexpression reprogrammes ketone metabolism, increasing AcAc and decreasing β-OHB, thereby reducing H3K9 β-hydroxybutyrylation at the LCN2 promoter and repressing LCN2 transcription; reduced LCN2 weakens NF-κB activity by reducing the LCN2-dependent interaction between NF-κB and RPS3. BDH1 KO and AAV-BDH1 overexpression in db/db mice, H3K9bhb ChIP at LCN2 promoter, transcriptome analysis, LCN2 overexpression rescue in vitro and in vivo, NF-κB-RPS3 Co-IP, β-hydroxybutyrylation inhibitor (A485) in vivo Cardiovascular diabetology Medium 40022118
2022 Kdm6a (H3K27 demethylase) in microglia/macrophages regulates Lcn2 expression in a demethylase-activity-dependent manner; Kdm6a deficiency epigenetically silences Lcn2, thereby protecting photoreceptors by maintaining glycolysis. Conditional Kdm6a knockout mice (microglia/macrophage-specific), RNA-seq, mass spectrometry, enzyme activity assays, immunohistochemistry, Kdm6a catalytic mutant analysis Metabolism: clinical and experimental Medium 35995279
2021 Tissue-infiltrating neutrophils (TI-Neu) secrete LCN2 to induce ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia; antibody depletion of TI-Neu and myeloid-specific Lcn2 knockout prevented ferroptosis and tissue wasting; chemical ferroptosis inhibition prolonged survival of cachectic mice. Lung cancer cachexia mouse models, LCN2 overexpression/blockade in vivo, neutrophil antibody depletion, myeloid-specific Lcn2 KO, ferroptosis inhibitor (ferrostatin-1) treatment, survival analysis Journal of hematology & oncology High 36973755
2021 In vivo, LCN2 increases autophagic flux blockade (autophagosome accumulation) in DOX-treated hearts: LCN2 KO hearts show increased autophagic flux (LC3B-II levels restored, LC3B-LAMP1 co-localization restored) and partial cardioprotection; LCN2 co-localizes with LC3B-stained cells in DOX-treated WT hearts. LCN2 KO mice, DOX injection, echocardiography, immunohistochemistry (LC3B, LAMP1 co-localization), Western blot (LC3BII, STAT3 phosphorylation), histology Biochemical and biophysical research communications Medium 34933182

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. The Journal of biological chemistry 978 7683678
2005 A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell 558 16377569
2008 Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. American journal of kidney diseases : the official journal of the National Kidney Foundation 463 18725016
2021 A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nature communications 267 34921145
2009 NGAL: a biomarker of acute kidney injury and other systemic conditions. International urology and nephrology 169 19582588
2023 The Review of Current Knowledge on Neutrophil Gelatinase-Associated Lipocalin (NGAL). International journal of molecular sciences 158 37445650
1989 SV40-induced expression of mouse gene 24p3 involves a post-transcriptional mechanism. Oncogene 143 2542864
2018 More than a simple biomarker: the role of NGAL in cardiovascular and renal diseases. Clinical science (London, England : 1979) 108 29739822
2011 Lipocalin-2 (24p3/neutrophil gelatinase-associated lipocalin (NGAL)) receptor is expressed in distal nephron and mediates protein endocytosis. The Journal of biological chemistry 104 22084236
1991 Mouse oncogene protein 24p3 is a member of the lipocalin protein family. Biochemical and biophysical research communications 103 1834059
2016 Lipocalin 2 (LCN2) Expression in Hepatic Malfunction and Therapy. Frontiers in physiology 102 27729871
2022 Neutrophil gelatinase-associated lipocalin (NGAL) in kidney injury - A systematic review. Clinica chimica acta; international journal of clinical chemistry 100 36150522
2017 The Update of NGAL in Acute Kidney Injury. Current protein & peptide science 93 27634444
2006 Effects of mouse and human lipocalin homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair. Gastroenterology 89 16952550
2023 Reduced secretion of LCN2 (lipocalin 2) from reactive astrocytes through autophagic and proteasomal regulation alleviates inflammatory stress and neuronal damage. Autophagy 85 36781380
2010 From kidney to cardiovascular diseases: NGAL as a biomarker beyond the confines of nephrology. European journal of clinical investigation 83 20415702
2007 Acute endotoxemia is associated with upregulation of lipocalin 24p3/Lcn2 in lung and liver. Experimental and molecular pathology 81 17490638
2023 LCN2 secreted by tissue-infiltrating neutrophils induces the ferroptosis and wasting of adipose and muscle tissues in lung cancer cachexia. Journal of hematology & oncology 80 36973755
2015 Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy. Biochimica et biophysica acta 80 26278055
1996 An apparent autocrine mechanism amplifies the dexamethasone- and retinoic acid-induced expression of mouse lipocalin-encoding gene 24p3. Gene 80 8666241
2022 NOX activation in reactive astrocytes regulates astrocytic LCN2 expression and neurodegeneration. Cell death & disease 72 35440572
1998 The hydrophobic pocket of 24p3 protein from mouse uterine luminal fluid: fatty acid and retinol binding activity and predicted structural similarity to lipocalins. The journal of peptide research : official journal of the American Peptide Society 66 9894844
2010 Disease and gender-specific dysregulation of NGAL and MMP-9 in type 1 diabetes mellitus. Endocrine 62 20960272
2012 NGAL-Siderocalin in kidney disease. Biochimica et biophysica acta 61 22728330
2002 High expression in involuting reproductive tissues of uterocalin/24p3, a lipocalin and acute phase protein. The Biochemical journal 61 12067275
2007 N-GAL: diagnosing AKI as soon as possible. Critical care (London, England) 60 18001501
2013 Impaired neutrophil function in 24p3 null mice contributes to enhanced susceptibility to bacterial infections. Journal of immunology (Baltimore, Md. : 1950) 58 23543755
2013 Albuminuria induces a proinflammatory and profibrotic response in cortical collecting ducts via the 24p3 receptor. American journal of physiology. Renal physiology 56 23884139
2005 24p3 and its receptor: dawn of a new iron age? Cell 53 16377555
2017 Resistin and NGAL are associated with inflammatory response, endothelial activation and clinical outcomes in sepsis. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 52 28424824
2014 Lipocalin-2 (LCN2) regulates PLIN5 expression and intracellular lipid droplet formation in the liver. Biochimica et biophysica acta 50 25086218
2009 Lipocalin 2 regulation by thermal stresses: protective role of Lcn2/NGAL against cold and heat stresses. Experimental cell research 50 19732769
2014 KIM-1 and NGAL as biomarkers of nephrotoxicity induced by gentamicin in rats. Molecular and cellular biochemistry 48 25087119
1999 Ovarian steroids regulate 24p3 expression in mouse uterus during the natural estrous cycle and the preimplantation period. The Journal of endocrinology 48 10396016
2018 Revisiting Neutrophil Gelatinase-Associated Lipocalin (NGAL) in Cancer: Saint or Sinner? Cancers 44 30231474
2017 NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis. Clinical chemistry and laboratory medicine 42 28672747
2003 Increased expression of the lipocalin 24p3 as an apoptotic mechanism for MK886. The Biochemical journal 40 12614196
2016 Lipocalin 2 (LCN2) is a promising target for cholangiocarcinoma treatment and bile LCN2 level is a potential cholangiocarcinoma diagnostic marker. Scientific reports 39 27782193
2009 Neutrophil gelatinase-associated lipocalin (NGAL/Lcn2) is upregulated in gastric mucosa infected with Helicobacter pylori. Virchows Archiv : an international journal of pathology 39 19727808
2024 MafG/MYH9-LCN2 axis promotes liver fibrosis through inhibiting ferroptosis of hepatic stellate cells. Cell death and differentiation 38 38871948
2009 Transcription and signalling pathways involved in BCR-ABL-mediated misregulation of 24p3 and 24p3R. The EMBO journal 37 19229297
2022 LCN2 Mediates Skin Inflammation in Psoriasis through the SREBP2‒NLRC4 Axis. The Journal of investigative dermatology 36 35120997
2019 CD4+ T Cell-Derived NGAL Modifies the Outcome of Ischemic Acute Kidney Injury. Journal of immunology (Baltimore, Md. : 1950) 34 31889023
2018 Expression of neutrophil gelatinase-associated lipocalin (NGAL) in the gut in Crohn's disease. Cell and tissue research 34 29869714
2023 Silencing LCN2 suppresses oral squamous cell carcinoma progression by reducing EGFR signal activation and recycling. Journal of experimental & clinical cancer research : CR 33 36899380
2022 Kdm6a deficiency in microglia/macrophages epigenetically silences Lcn2 expression and reduces photoreceptor dysfunction in diabetic retinopathy. Metabolism: clinical and experimental 33 35995279
2022 Lcn2 mediates adipocyte-muscle-tumor communication and hypothermia in pancreatic cancer cachexia. Molecular metabolism 33 36243318
2000 Expression, immunolocalization and sperm-association of a protein derived from 24p3 gene in mouse epididymis. Molecular reproduction and development 33 10954853
2018 CRABP1, C1QL1 and LCN2 are biomarkers of differentiated thyroid carcinoma, and predict extrathyroidal extension. BMC cancer 30 29321030
2013 Expression and function of the lipocalin-2 (24p3/NGAL) receptor in rodent and human intestinal epithelia. PloS one 30 23940770
2021 NGAL as a Potential Target in Tumor Microenvironment. International journal of molecular sciences 29 34830212
2007 Apoptosis induced by uterine 24p3 protein in endometrial carcinoma cell line. Toxicology 29 17420078
2025 Regulating astrocyte phenotype by Lcn2 inhibition toward ischemic stroke therapy. Biomaterials 28 39836995
2021 TGF-β-induced PLEK2 promotes metastasis and chemoresistance in oesophageal squamous cell carcinoma by regulating LCN2. Cell death & disease 27 34601488
2024 Berberine alleviates neuroinflammation by downregulating NFκB/LCN2 pathway in sepsis-associated encephalopathy: network pharmacology, bioinformatics, and experimental validation. International immunopharmacology 26 38640713
2020 LncRNA TMPO-AS1 promotes LCN2 transcriptional activity and exerts oncogenic functions in ovarian cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 32692467
2018 NGAL protects against endotoxin-induced renal tubular cell damage by suppressing apoptosis. BMC nephrology 26 29980183
2021 Nerve growth factor orchestrates NGAL and matrix metalloproteinases activity to promote colorectal cancer metastasis. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 25 34255268
2024 LCN2: Versatile players in breast cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 24 38171248
2023 A protein complex of LCN2, LOXL2 and MMP9 facilitates tumour metastasis in oesophageal cancer. Molecular oncology 23 37753805
2024 Tumor-secreted LCN2 impairs gastric cancer progression via autocrine inhibition of the 24p3R/JNK/c-Jun/SPARC axis. Cell death & disease 22 39424639
2017 Clinical Relevance of NGAL/MMP-9 Pathway in Patients with Endometrial Cancer. Disease markers 22 29089666
2007 Lipocalin 24p3 is regulated by the Wnt pathway independent of regulation by iron. Cancer genetics and cytogenetics 22 17350462
2018 Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection. Cell communication and signaling : CCS 21 30404645
2011 Multiple apoptotic defects in hematopoietic cells from mice lacking lipocalin 24p3. The Journal of biological chemistry 20 21507940
2021 Increased Endocytosis of Cadmium-Metallothionein through the 24p3 Receptor in an In Vivo Model with Reduced Proximal Tubular Activity. International journal of molecular sciences 19 34298880
2020 Association between neutrophil gelatinase-associated lipocalin (NGAL) and iron profile in chronic renal disease. Archives of physiology and biochemistry 19 31994917
2025 BDH1 overexpression alleviates diabetic cardiomyopathy through inhibiting H3K9bhb-mediated transcriptional activation of LCN2. Cardiovascular diabetology 18 40022118
2025 LCN2 induces neuronal loss and facilitates sepsis-associated cognitive impairments. Cell death & disease 18 40025014
2025 Faecalibacterium prausnitzii prevents age-related heart failure by suppressing ferroptosis in cardiomyocytes through butyrate-mediated LCN2 regulation. Gut microbes 18 40364435
2024 Lipocalin 2 (LCN2) confers acquired resistance to almonertinib in NSCLC through LCN2-MMP-9 signaling pathway. Pharmacological research 17 38295916
2024 Withaferin A protects against epilepsy by promoting LCN2-mediated astrocyte polarization to stopping neuronal ferroptosis. Phytomedicine : international journal of phytotherapy and phytopharmacology 17 39032282
2017 Corticoids synergize with IL-1 in the induction of LCN2. Osteoarthritis and cartilage 17 28185846
2012 Expression of NGAL and NGALR in human embryonic, fetal and normal adult tissues. Molecular medicine reports 17 22797813
2025 Microglial Lcn2 knockout enhances chronic intracerebral hemorrhage recovery by restoring myelin and reducing inflammation. Theranostics 16 40225581
2021 LCN2 deficiency ameliorates doxorubicin-induced cardiomyopathy in mice. Biochemical and biophysical research communications 16 34933182
2025 LCN2 deficiency mitigates the neuroinflammatory damage following acute glaucoma. Theranostics 15 40083945
2025 MVP-LCN2 axis triggers evasion of ferroptosis to drive hepatocarcinogenesis and sorafenib resistance. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 15 40262414
2025 FBXO2 Alleviates Intervertebral Disc Degeneration via Dual Mechanisms: Activating PINK1-Parkin Mitophagy and Ubiquitinating LCN2 to Suppress Ferroptosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 15 40791152
2024 Knockdown of LncRNA Lcn2-204 alleviates sepsis-induced myocardial injury by regulation of iron overload and ferroptosis. Journal of molecular and cellular cardiology 15 38761990
2023 NGAL is a Novel Target in Hypertension by Modulating the NCC-Mediated Renal Na Balance. Hypertension (Dallas, Tex. : 1979) 15 37377014
2021 LCN2 Is a Potential Biomarker for Radioresistance and Recurrence in Nasopharyngeal Carcinoma. Frontiers in oncology 15 33604288
2020 Differential regulation of Lipocalin 2 (LCN2) in doxorubicin-resistant 4T1 triple negative breast cancer cells. Cellular signalling 15 32758668
2010 NGAL immunohistochemical expression in brain primary and metastatic tumors. Clinical neuropathology 15 20860895
2019 LCN2-interacting proteins and their expression patterns in brain tumors. Brain research 14 31233712
2018 The expression analysis of NGAL and NGALR in clear cell renal cell carcinoma. Gene 14 30138675
2015 C-reactive protein but not hepcidin, NGAL and transferrin determines the ESA resistance in hemodialysis patients. Renal failure 14 26539647
2014 NGAL can alternately mediate sunitinib resistance in renal cell carcinoma. The Journal of urology 14 24423438
2007 Mouse 24p3 protein has an effect on L929 cell viability. International journal of biological sciences 14 17304338
2003 Macrophage-induced rat mesangial cell expression of the 24p3-like protein alpha-2-microglobulin-related protein. Biochimica et biophysica acta 14 12573252
2024 Gandouling Regulates Ferroptosis and Improves Neuroinflammation in Wilson's Disease Through the LCN2/NLRP3 Signaling Pathway. Journal of inflammation research 13 39193124
2018 Expression and clinical correlation of NGAL and VEGF in endometrial carcinoma. European review for medical and pharmacological sciences 13 29461590
2008 Identification of 24p3 as a direct target of Foxo3a regulated by interleukin-3 through the phosphoinositide 3-kinase/Akt pathway. The Journal of biological chemistry 13 19056725
2004 The 24p3 gene is induced during involution of the mammary gland and induces apoptosis of mammary epithelial cells. Molecules and cells 13 15055523
2024 G-4 inhibits triple negative breast cancer by inducing cell apoptosis and promoting LCN2-dependent ferroptosis. Biochemical pharmacology 12 38395264
2023 Expression Analysis of Lipocalin 2 (LCN2) in Reproductive and Non-Reproductive Tissues of Esr1-Deficient Mice. International journal of molecular sciences 12 37298232
2018 Quantification of NGAL in Urine of Endurance Cycling Athletes. Journal of physical activity & health 12 30068247
1997 Complex formation between a formyl peptide and 24p3 protein with a blocked N-terminus of pyroglutamate. The journal of peptide research : official journal of the American Peptide Society 12 9266486
2024 LCN2 depletion aggravates sepsis-induced liver injury by regulating PTGS2-dependent ferroptosis. International journal of medical sciences 11 39512683
2020 Serum Levels and Placental Expression of NGAL in Gestational Diabetes Mellitus. International journal of endocrinology 11 32377189

Missed literature

Know a paper Affinage missed for LCN2? Flag it for the maintainers and the community.

No submissions yet.