{"gene":"LECT2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1996,"finding":"LECT2 was purified from culture fluid of PHA-activated human T-cell leukemia SKW-3 cells as a 16-kDa basic protein with neutrophil chemotactic activity, establishing it as a novel chemotactic factor distinct from all previously known chemotactic factors.","method":"Protein purification, SDS-PAGE, amino acid sequence analysis, neutrophil chemotaxis assay","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct biochemical purification and in vitro activity assay, single lab, single study","pmids":["8877413"],"is_preprint":false},{"year":1997,"finding":"Recombinant LECT2 produced in CHO and L929 cells is a secreted 16-kDa protein expressed in hepatocytes; immunostaining demonstrated diffuse cytoplasmic LECT2 in human hepatocytes, and five of six hepatoma cell lines secreted LECT2 into culture fluids.","method":"Stable transfection, recombinant protein production, ELISA, immunostaining with polyclonal and monoclonal antibodies","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by immunostaining and secretion quantified by sandwich ELISA, single lab","pmids":["9266841"],"is_preprint":false},{"year":1998,"finding":"LECT2 is encoded by a ~8 kb gene with four exons and three introns, mapped to human chromosome 5q31.1-q32 by FISH; liver-specific expression is driven by transcriptional control sequences in the 5' untranslated region.","method":"Gene cloning, primer extension, fluorescence in situ hybridization (FISH)","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct genomic characterization and chromosomal mapping, single lab","pmids":["9545637"],"is_preprint":false},{"year":2003,"finding":"LECT2 is a 133-amino-acid protein with three intramolecular disulfide bonds; properly refolded recombinant LECT2 from E. coli retains the same tertiary structure as CHO-cell-produced authentic LECT2, confirmed by CD and NMR spectroscopy.","method":"Recombinant protein expression and oxidative refolding, CD spectroscopy, NMR spectroscopy, chemotaxis assay","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structural characterization with functional validation (chemotaxis), single lab","pmids":["12597887"],"is_preprint":false},{"year":2012,"finding":"LECT2 activates macrophages (but not polymorphonuclear neutrophils) via the CD209a receptor to enhance phagocytosis, bacterial killing, and gene expression changes; CD209a was identified as a specific binding partner for LECT2 and CD209a-expressing macrophages mediated protection against bacterial sepsis in vivo.","method":"Receptor identification by specific interaction assay, in vitro macrophage activation assays (phagocytosis, bacterial killing), in vivo sepsis mouse model with CD209a-expressing macrophage depletion","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor identified by specific interaction, confirmed with in vitro functional assays and in vivo epistasis (macrophage depletion), single lab but multiple orthogonal methods","pmids":["23254286"],"is_preprint":false},{"year":2014,"finding":"LECT2 functions as a hepatokine linking obesity to skeletal muscle insulin resistance: LECT2 expression is negatively regulated by the energy-sensing kinase AMPK in hepatocytes; recombinant LECT2 impairs insulin signaling in C2C12 myocytes via JNK phosphorylation; genetic deletion of LECT2 in mice increases skeletal muscle insulin sensitivity.","method":"Recombinant protein treatment of myocytes (Western blot for JNK phosphorylation), LECT2 knockout mice (insulin sensitivity measurement), AMPK manipulation in HepG2/H4IIEC hepatocytes","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype plus in vitro mechanistic signaling assay plus in vivo correlation, multiple orthogonal methods in one study","pmids":["24478397"],"is_preprint":false},{"year":2015,"finding":"LECT2 induces inflammatory responses in human endothelial cells and THP-1 cells via CD209 receptor-mediated JNK phosphorylation, increasing ICAM-1, TNFα, MCP-1, and IL-1β expression and enhancing monocyte adhesion to endothelial cells; CD209 siRNA knockdown abolished these effects.","method":"Recombinant LECT2 treatment of HUVECs and THP-1 cells, Western blot, qPCR, siRNA knockdown of CD209, JNK inhibitor experiments, monocyte adhesion assay","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor knockdown with siRNA confirmed signaling dependence, multiple readouts, single lab","pmids":["26123523"],"is_preprint":false},{"year":2015,"finding":"LECT2 increases mTOR phosphorylation and SREBP-1 cleavage in HepG2 cells via JNK signaling, promoting lipid accumulation and insulin resistance; gemigliptin (DPP-4 inhibitor) reduces LECT2 expression via AMPK-dependent and JNK-dependent mechanisms.","method":"Western blot for signaling pathway components in HepG2 cells, LECT2 knockdown, JNK inhibitor and AMPK inhibitor treatments, in vivo high-fat diet mouse model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling pathway interventions (inhibitors, KD) with consistent results, single lab","pmids":["26297911"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of human LECT2 reveals an M23 metalloendopeptidase fold with conserved Zn(II) coordination but lacking a catalytic histidine residue; the potential substrate-binding groove is blocked by an N-terminal intrachain loop; LECT2 is catalytically inactive as a metalloendopeptidase. Surface plasmon resonance showed LECT2 binds the c-Met receptor with micromolar affinity.","method":"X-ray crystallography (1.94 Å resolution), peptidase activity assay against multiple peptide sequences including pentaglycine, surface plasmon resonance (SPR)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determination plus enzymatic assay confirming catalytic inactivity plus SPR binding measurement, multiple orthogonal methods in one rigorous study","pmids":["27334921"],"is_preprint":false},{"year":2016,"finding":"LECT2 drives haematopoietic stem cell (HSC) expansion in bone marrow and mobilization to blood via CD209a receptor; this effect requires macrophages and osteolineage cells and is mediated through reduction of TNF expression in these cells (demonstrated by loss of effect in TNF-KO mice).","method":"Recombinant LECT2 administration in mice, HSC quantification by flow cytometry, specific macrophage depletion, TNF knockout mice, CD209a receptor mediation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo epistasis experiments (macrophage depletion, TNF KO, CD209a receptor), consistent results across methods","pmids":["27596364"],"is_preprint":false},{"year":2016,"finding":"LECT2 suppresses VEGF165-induced endothelial cell proliferation, migration, and tube formation by directly binding VEGFR2 and reducing VEGFR2 tyrosine phosphorylation and downstream ERK/AKT phosphorylation, thereby inhibiting angiogenesis in HCC.","method":"Recombinant LECT2 treatment of endothelial cells, VEGFR2 phosphorylation assay (Western blot), in vitro angiogenesis assays (proliferation, migration, tube formation), in vivo HCC xenograft model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding to VEGFR2 implied by reduced phosphorylation, multiple functional assays, single lab","pmids":["27507763"],"is_preprint":false},{"year":2016,"finding":"LECT2 macrophage activation via a C-type lectin receptor (PaCLR/CD209a homolog in ayu fish) is mediated through NF-κB activation via Raf-1; CD209a Ser28 phosphorylation in the intracellular domain is required for LECT2-induced Raf-1 and NF-κB activation in macrophages.","method":"Anti-receptor neutralization, western blot for signaling components, transfection experiments, phosphorylation-site specific antibodies","journal":"Genetics and molecular research / Fish & shellfish immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific phosphorylation site identified with functional consequences, receptor neutralization confirmed pathway, single lab","pmids":["27813598","26876329"],"is_preprint":false},{"year":2018,"finding":"LECT2 promotes inflammation and insulin resistance in adipocytes via a CD209/P38-dependent pathway; LECT2 activates P38 phosphorylation, NF-κB/IκB phosphorylation, and IL-6 expression, impairs insulin signaling (reduced IRS-1 and Akt phosphorylation), reduces glucose uptake, and augments lipid accumulation via SREBP1c. All effects were abrogated by P38 siRNA or CD209 siRNA.","method":"Recombinant LECT2 treatment of differentiated 3T3-L1 cells, siRNA knockdown of P38 and CD209, Western blot, glucose uptake assay","journal":"Journal of molecular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor and signaling pathway confirmed by siRNA knockdown with multiple functional readouts, single lab","pmids":["29650721"],"is_preprint":false},{"year":2019,"finding":"LECT2 is a functional ligand for the endothelial receptor Tie1; LECT2 binding to Tie1 disrupts Tie1/Tie2 heterodimerization, promotes Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits endothelial cell migration and tube formation. In vivo, LECT2 overexpression inhibits portal angiogenesis and promotes sinusoid capillarization, worsening liver fibrosis; Lect2-KO mice showed reversal of these effects; AAV9-LECT2-shRNA treatment attenuated fibrosis.","method":"Ligand-receptor binding assay, Co-immunoprecipitation (Tie1/Tie2 dimerization), endothelial cell functional assays (migration, tube formation), Lect2-KO mice, AAV-shRNA in vivo knockdown, PPAR signaling assay","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — receptor identification by binding and co-IP, multiple in vitro functional assays, Lect2-KO rescue, and in vivo therapeutic intervention, multiple orthogonal methods","pmids":["31474362"],"is_preprint":false},{"year":2020,"finding":"Knockdown of LECT2 in MSCs activates the Wnt/β-catenin pathway and promotes osteogenic differentiation; LECT2 expression is decreased during osteogenic differentiation of MSCs, and its downregulation facilitates osteoblast differentiation.","method":"LECT2 knockdown in MSCs, Wnt/β-catenin pathway activation assay, osteogenic differentiation assay","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (KD with pathway assay), single lab, limited mechanistic detail in abstract","pmids":["32763823"],"is_preprint":false},{"year":2021,"finding":"Loss of bound zinc (Zn2+) is obligatory for LECT2 fibril formation in vitro; zinc-binding affinity is strongly pH-dependent (9-13% zinc-free under normal blood pH, rising to 80% at pH 6.5). The I40V mutation does not alter zinc-binding affinity but destabilizes the zinc-free conformation. These findings suggest a mechanism where zinc loss combined with I40V mutation promotes ALECT2 amyloidosis.","method":"Electron microscopy, X-ray diffraction, NMR, fluorescence spectroscopy, zinc-binding affinity measurements, pH-dependent fibril formation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro fibril formation with multiple structural methods (EM, X-ray diffraction, NMR, fluorescence), mechanistic dissection of zinc dependence and I40V mutation effects","pmids":["33617884"],"is_preprint":false},{"year":2021,"finding":"LECT2 selectively enhances LPS-induced JNK phosphorylation (but not ERK or p38) in Kupffer cells by potentiating upstream MKK4 and TAB2 phosphorylation, shifting liver macrophages to an M1-like phenotype and contributing to NASH-associated liver inflammation.","method":"LECT2 KO mice (flow cytometry for M1/M2 macrophage ratios, inflammatory cytokine mRNA), in vitro KUP5 cell signaling (Western blot for JNK, ERK, p38, MKK4, TAB2 phosphorylation), human liver biopsy correlation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse phenotype plus specific in vitro signaling pathway dissection, single lab, multiple methods","pmids":["33436955"],"is_preprint":false},{"year":2021,"finding":"ER stress increases LECT2 expression in hepatocytes via the ATF4 transcription factor; ChIP assay demonstrated ATF4 directly binds three putative binding sites on the LECT2 promoter, and binding is promoted by ER stress inducers. ATF4 knockdown suppressed ER stress-induced LECT2 expression; ATF4 overexpression enhanced it.","method":"ER stress induction in HepG2 cells, siRNA knockdown of UPR pathway genes, ATF4 overexpression, ChIP-qPCR assay, in vivo obese mouse liver expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR directly demonstrated ATF4 binding to LECT2 promoter, corroborated by KD/OE experiments, single lab","pmids":["34808500"],"is_preprint":false},{"year":2022,"finding":"LECT2 ameliorates hyperglycemia-induced blood-retinal barrier impairment by activating the Tie2/Akt/mTOR signaling pathway, increasing interendothelial tight junction proteins (ZO1, VE-cadherin, occludin) and attenuating endothelial cell permeability, migration, and tube formation.","method":"Recombinant LECT2 treatment of HRMECs and HUVECs under high-glucose conditions, Western blot for Tie2/Akt/mTOR pathway and junction proteins, FITC-dextran permeability assay, intravitreal injection in streptozotocin-induced diabetic mice, electron microscopy","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro signaling pathway with multiple junction protein readouts confirmed in vivo by intravitreal injection, single lab","pmids":["35262733"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of recombinant human LECT2 amyloid fibrils reveals two mating protofilaments with ordered core spanning residues 55-75 of the LECT2 sequence; the fibril core is stabilized by hydrophobic contacts and hydrogen-bonded uncharged polar residues, and fibrils are resistant to 3M urea and proteinase K.","method":"Single-particle cryo-EM, protease/denaturant resistance assays","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure determination with functional validation (denaturant and protease resistance), peer-reviewed","pmids":["37657439"],"is_preprint":false},{"year":2023,"finding":"LECT2 modulates dendritic cell function during H. pylori infection via CD209a receptor; LECT2 promoted BMDC maturation and skewed cytokine production toward IL-10 (anti-inflammatory) and away from IL-23p40, shifting T-cell differentiation from Th1/Th17 toward Treg. CD209a-deficient BMDCs did not respond to LECT2. The signaling pathway involves CD209a-JNK/P38 MAPK.","method":"LECT2 treatment of bone marrow-derived DCs from WT, CD209a-KO, and LECT2-KO mice; flow cytometry; Western blot; real-time PCR; T-cell co-culture differentiation assay","journal":"Journal of gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CD209a-KO DCs confirm receptor specificity, multiple functional and signaling readouts, single lab","pmids":["36740832"],"is_preprint":false},{"year":2024,"finding":"Physiological kidney-like flow shear (generated by microfluidic device with progressively narrowing channels) efficiently induces LECT2 fibril formation in combination with zinc loss; the I40V mutation accelerates fibril formation and increases aggregate size and density under flow shear conditions. Fibril morphology differs between laminar flow shear and shaking/stirring.","method":"Microfluidic device mimicking renal flow shear, electron microscopy of resulting fibrils, comparison of WT vs I40V LECT2 fibrillation kinetics","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro fibrillation under physiological shear conditions with EM characterization; I40V mutation effect demonstrated directly, single lab","pmids":["38537700"],"is_preprint":false},{"year":2025,"finding":"LECT2 promotes liver regeneration by activating the ADAM10-NOTCH signaling pathway; hepatocyte-specific Lect2-KO impairs liver regeneration after partial hepatectomy across multiple age groups, and ADAM10 suppression abolishes the pro-regenerative effect of LECT2 overexpression. AAV-mediated Lect2 overexpression enhanced post-hepatectomy regenerative capacity.","method":"RNA-seq, scRNA-seq, hepatocyte-specific Lect2-KO mice, co-immunoprecipitation, ADAM10 inhibition experiments, AAV-mediated Lect2 overexpression, Ki-67/PCNA staining","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via ADAM10 inhibition rescuing Lect2-OE, KO mice phenotype, co-IP showing pathway interaction, single lab","pmids":["41811354"],"is_preprint":false},{"year":2025,"finding":"LPS directly induces LECT2 expression in hepatocytes via TLR4 receptor signaling; downstream p38 MAPK activates AP-1 (c-Fos/c-Jun), which directly binds a putative AP-1-like site on the Lect2 promoter as confirmed by ChIP-qPCR, driving LECT2 transcription during inflammation.","method":"TLR4-specific inhibitor, p38 MAPK inhibitor/agonist, c-Fos/c-Jun overexpression, ChIP-qPCR, Lect2 promoter analysis in AML12 hepatocytes","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR confirmed direct AP-1 binding to Lect2 promoter, pharmacological pathway confirmation, single lab","pmids":["40495481"],"is_preprint":false},{"year":2025,"finding":"Ex-vivo ALECT2 amyloid fibrils extracted from a patient kidney show structural polymorphism: a predominant single-protofilament morphology comprising full-length 133-residue LECT2 retaining all three native disulfide bonds, and two minor double-protofilament morphologies with similar fold but different inter-filament interfaces. Mass spectrometry revealed acetylation within fibrils.","method":"Cryo-EM of ex-vivo patient-derived fibrils, mass spectrometry","journal":"bioRxiv (preprint)","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — cryo-EM structure of ex-vivo fibrils with MS validation, but preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.07.15.664973"],"is_preprint":true},{"year":2009,"finding":"LECT2 regulates axon and dendrite extension in hippocampal neurons; neurons from LECT2-KO mice showed significantly shorter axons and dendrites than wild-type, and displayed altered expression of neurotrophins NGF, BDNF, and NT-3 during neuronal development.","method":"LECT2-KO mouse hippocampal neuron culture, morphometric analysis of neurite extension, neurotrophin expression analysis","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO mouse with defined morphological phenotype and expression readouts, single lab, single study","pmids":["19917270"],"is_preprint":false},{"year":2010,"finding":"LECT2 regulates neuritic extension through control of microtubule morphology by modulating katanin-P60 levels; LECT2-KO hippocampal neurons showed fragmented, shorter microtubules and elevated katanin-P60 expression compared to wild-type neurons.","method":"LECT2-KO mouse hippocampal neuron culture, microtubule morphology analysis, Western blot for katanin-P60 expression","journal":"Neuroreport","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KO comparison with protein expression readout, no direct rescue or mechanistic intervention, single lab","pmids":["20463617"],"is_preprint":false},{"year":2025,"finding":"LECT2 overexpression in endothelial cells promotes kidney fibrosis via activation of the EGFR/AKT/PI3K pathway; Lect2-KO mice showed reduced fibrosis, reduced myofibroblast activation, and less collagen deposition in a kidney fibrosis model, with increased CHOP expression and earlier endothelial cell activation.","method":"Lect2-KO mice kidney fibrosis model, LECT2 overexpression in EA.hy926 cells, Western blot for EGFR/AKT/PI3K pathway, histological analysis, Lect2 reporter mice","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice and OE cell experiments with defined signaling pathway, multiple histological readouts, single lab","pmids":["40398731"],"is_preprint":false}],"current_model":"LECT2 is a 16-kDa liver-derived secreted protein (hepatokine) that functions as a pleiotropic ligand for multiple cell-surface receptors—including Tie1 (on endothelial cells), CD209/CD209a (on macrophages and immune cells), VEGFR2, and c-Met—adopting a catalytically inactive M23 metalloendopeptidase fold that coordinates a single Zn2+ ion; receptor binding activates downstream signaling cascades (JNK, p38 MAPK, NF-κB, PPAR, Tie2/Akt/mTOR, ADAM10-NOTCH) that regulate neutrophil chemotaxis, macrophage activation and polarization, endothelial cell migration and angiogenesis, skeletal muscle insulin resistance, liver fibrosis, liver regeneration, HSC homeostasis, and neuronal morphology, while loss of its bound zinc together with the I40V polymorphism promotes amyloid fibril formation (ALECT2 amyloidosis) under physiological flow shear conditions."},"narrative":{"mechanistic_narrative":"LECT2 is a liver-derived, 16-kDa secreted protein (hepatokine) that functions as a pleiotropic ligand for cell-surface receptors, transducing metabolic and inflammatory cues into signaling across immune, endothelial, hepatic, and neuronal compartments [PMID:9266841, PMID:24478397]. Structurally it adopts an M23 metalloendopeptidase fold that coordinates a single Zn(II) ion but lacks the catalytic histidine and has a substrate groove occluded by an N-terminal loop, rendering it catalytically inactive; it engages the c-Met receptor with micromolar affinity [PMID:27334921]. Through the C-type lectin receptor CD209/CD209a it activates macrophages, dendritic cells, and adipocytes via JNK, p38, and NF-κB signaling, modulating phagocytosis and bacterial killing, immune polarization, and inflammation-driven insulin resistance [PMID:23254286, PMID:29650721, PMID:36740832]. As a metabolic effector, hepatic LECT2 is repressed by AMPK and impairs insulin signaling in skeletal muscle through JNK, with LECT2 deletion increasing muscle insulin sensitivity [PMID:24478397]. On endothelium LECT2 acts as a Tie1 ligand that disrupts Tie1/Tie2 heterodimerization and drives PPAR signaling to inhibit angiogenesis and worsen liver fibrosis, while also binding VEGFR2 to suppress VEGF-driven endothelial proliferation [PMID:27507763, PMID:31474362]. It additionally drives haematopoietic stem cell expansion via CD209a, promotes liver regeneration through ADAM10-NOTCH signaling, and regulates hippocampal neurite extension via control of katanin-P60 and microtubule morphology [PMID:27596364, PMID:41811354, PMID:19917270]. Hepatic LECT2 transcription is induced by ER stress through ATF4 and by LPS/TLR4-p38-AP-1 signaling [PMID:34808500, PMID:40495481]. Loss of bound zinc is obligatory for conversion of LECT2 into amyloid fibrils, a process accelerated by the I40V polymorphism and physiological renal flow shear and underlying ALECT2 amyloidosis [PMID:33617884, PMID:38537700].","teleology":[{"year":1996,"claim":"Established LECT2 as a novel secreted neutrophil chemotactic factor, defining it as a distinct extracellular signaling protein.","evidence":"Protein purification from PHA-activated T-cell leukemia cells with chemotaxis assay","pmids":["8877413"],"confidence":"Medium","gaps":["No receptor identified","Mechanism of chemotaxis undefined","In vitro activity only"]},{"year":1997,"claim":"Identified the hepatocyte as the principal source of secreted LECT2, framing it as a liver-derived factor.","evidence":"Recombinant expression, ELISA, and immunostaining of human hepatocytes and hepatoma lines","pmids":["9266841"],"confidence":"Medium","gaps":["Functional consequence of hepatic secretion not addressed","Regulation of expression unknown"]},{"year":1998,"claim":"Defined the gene structure and mapped liver-specific expression to 5' regulatory sequences, anchoring tissue-restricted control.","evidence":"Gene cloning, primer extension, and FISH mapping to chromosome 5q31.1-q32","pmids":["9545637"],"confidence":"Medium","gaps":["Specific transcription factors not identified","No upstream signaling defined"]},{"year":2003,"claim":"Resolved the disulfide-bonded folded tertiary structure of LECT2, enabling functional recombinant production.","evidence":"Oxidative refolding of E. coli protein with CD/NMR spectroscopy and chemotaxis validation","pmids":["12597887"],"confidence":"Medium","gaps":["No atomic-resolution fold yet","Receptor engagement not structurally mapped"]},{"year":2012,"claim":"Identified CD209a as a specific LECT2 receptor on macrophages, establishing a defined receptor-mediated immune function with in vivo protection against sepsis.","evidence":"Receptor binding assay, macrophage phagocytosis/killing assays, and CD209a-macrophage depletion sepsis model","pmids":["23254286"],"confidence":"High","gaps":["Binding interface not structurally defined","Intracellular signaling steps not fully resolved at the time"]},{"year":2014,"claim":"Cast LECT2 as a hepatokine linking obesity to muscle insulin resistance via AMPK-controlled expression and JNK-dependent signaling.","evidence":"LECT2-KO mice insulin sensitivity, C2C12 JNK phosphorylation, and AMPK manipulation in hepatocytes","pmids":["24478397"],"confidence":"High","gaps":["Muscle receptor mediating the effect not identified","Direct receptor on myocytes undefined"]},{"year":2015,"claim":"Extended CD209/JNK signaling to endothelial and hepatic lipogenic inflammation, mechanistically tying LECT2 to vascular inflammation and lipid accumulation.","evidence":"CD209 siRNA knockdown in HUVEC/THP-1 with JNK readouts and mTOR/SREBP-1 signaling in HepG2 cells","pmids":["26123523","26297911"],"confidence":"Medium","gaps":["Direct CD209 binding affinity not measured","Cell-type specificity of receptor usage unresolved"]},{"year":2016,"claim":"Solved the crystal structure revealing a catalytically dead M23 metalloendopeptidase fold with Zn coordination and demonstrated direct c-Met binding, redefining LECT2 as a receptor ligand rather than a protease.","evidence":"1.94 Å X-ray crystallography, peptidase assays, and SPR binding to c-Met","pmids":["27334921"],"confidence":"High","gaps":["Functional consequence of c-Met binding not established","Role of bound zinc in signaling not addressed"]},{"year":2016,"claim":"Demonstrated LECT2/CD209a control of HSC expansion and VEGFR2-mediated angiogenesis suppression, broadening receptor repertoire and physiological roles.","evidence":"In vivo macrophage depletion and TNF-KO HSC experiments; VEGFR2 phosphorylation assays and HCC xenografts","pmids":["27596364","27507763"],"confidence":"High","gaps":["Direct VEGFR2 binding affinity not quantified","Cross-talk among multiple receptors unresolved"]},{"year":2016,"claim":"Mapped the CD209a intracellular signaling route, identifying a required Ser28 phosphorylation event upstream of Raf-1/NF-κB.","evidence":"Receptor neutralization, phospho-site antibodies, and transfection in fish/macrophage models","pmids":["27813598","26876329"],"confidence":"Medium","gaps":["Conservation to mammalian CD209 signaling not fully shown","Kinase responsible for Ser28 phosphorylation unidentified"]},{"year":2019,"claim":"Identified Tie1 as a LECT2 receptor whose engagement shifts Tie dimerization toward Tie2 homodimers and drives PPAR signaling, mechanistically explaining LECT2-driven fibrosis and sinusoidal capillarization.","evidence":"Binding/co-IP, endothelial functional assays, Lect2-KO rescue, and AAV9-shRNA therapeutic intervention","pmids":["31474362"],"confidence":"High","gaps":["Structural basis of Tie1 engagement undefined","Hierarchy among CD209/Tie1/VEGFR2/c-Met engagement unresolved"]},{"year":2020,"claim":"Linked LECT2 downregulation to Wnt/β-catenin-driven osteogenic differentiation of MSCs.","evidence":"LECT2 knockdown in MSCs with Wnt pathway and osteogenic differentiation assays","pmids":["32763823"],"confidence":"Low","gaps":["Single method (knockdown) without rescue","Receptor mediating the effect not identified","No in vivo confirmation"]},{"year":2021,"claim":"Established the molecular basis of ALECT2 amyloidosis: zinc loss is obligatory for fibril formation, is pH-dependent, and the I40V mutation destabilizes the zinc-free state.","evidence":"In vitro reconstituted fibril formation with EM, X-ray diffraction, NMR, and zinc-binding measurements","pmids":["33617884"],"confidence":"High","gaps":["Physiological trigger of zinc loss in vivo not defined at the time","Fibril atomic structure not yet resolved"]},{"year":2021,"claim":"Defined LECT2 control of liver macrophage and hepatocyte inflammatory programs, including selective JNK potentiation in Kupffer cells and ER-stress/ATF4-driven hepatic LECT2 induction.","evidence":"LECT2-KO mice, KUP5 signaling dissection, and ATF4 ChIP-qPCR with KD/OE in HepG2 cells","pmids":["33436955","34808500"],"confidence":"Medium","gaps":["Receptor mediating Kupffer cell signaling not pinpointed","Integration of metabolic and stress inputs incomplete"]},{"year":2022,"claim":"Showed LECT2-Tie2/Akt/mTOR signaling stabilizes endothelial barriers, demonstrating context-dependent protective endothelial outcomes.","evidence":"Recombinant LECT2 on retinal/HUVEC endothelial cells with permeability and junction protein readouts and intravitreal injection in diabetic mice","pmids":["35262733"],"confidence":"Medium","gaps":["Reconciliation with anti-angiogenic Tie1 effects unresolved","Direct receptor responsible in this context not formally distinguished"]},{"year":2023,"claim":"Provided the cryo-EM fibril architecture (ordered core residues 55-75) and showed CD209a-dependent dendritic cell tolerogenic skewing, advancing both the amyloid and immunomodulatory mechanisms.","evidence":"Single-particle cryo-EM of recombinant fibrils; CD209a-KO BMDC assays with T-cell differentiation readouts","pmids":["37657439","36740832"],"confidence":"High","gaps":["Recombinant fibril core differs from ex-vivo fibrils (later finding)","Trigger converting native to fibrillar form in vivo not defined"]},{"year":2024,"claim":"Demonstrated that physiological renal flow shear, combined with zinc loss, efficiently nucleates LECT2 fibrils and that I40V accelerates this, linking kidney microenvironment to amyloid deposition.","evidence":"Microfluidic shear device with EM and WT vs I40V fibrillation kinetics","pmids":["38537700"],"confidence":"Medium","gaps":["In vivo confirmation of shear-driven fibrillation lacking","Quantitative contribution of shear vs zinc loss not separated"]},{"year":2025,"claim":"Expanded LECT2 mechanisms to liver regeneration (ADAM10-NOTCH), kidney fibrosis (EGFR/AKT/PI3K), TLR4-p38-AP-1 transcriptional induction, and resolved an ex-vivo patient fibril structure differing from recombinant fibrils.","evidence":"Hepatocyte-specific Lect2-KO with ADAM10 inhibition and co-IP; Lect2-KO kidney fibrosis model; ChIP-qPCR of AP-1 on Lect2 promoter; cryo-EM/MS of patient-derived fibrils (one preprint)","pmids":["41811354","40398731","40495481","bio_10.1101_2025.07.15.664973"],"confidence":"Medium","gaps":["Receptor mediating ADAM10-NOTCH activation not identified","Reconciliation of full-length disulfide-intact ex-vivo fibrils with the recombinant 55-75 core unresolved","Kidney fibrosis receptor undefined"]},{"year":null,"claim":"How LECT2 selects among its multiple receptors (CD209/CD209a, Tie1, VEGFR2, c-Met) in a given cell type, and what physiological cue triggers in vivo zinc loss and the native-to-amyloid transition, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of any LECT2-receptor complex","Receptor hierarchy/competition mechanism undefined","In vivo trigger of pathological fibrillation not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4,13,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[10,13]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[4,13]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,13,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,9,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5,12,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,19,21]}],"complexes":[],"partners":["CD209","TIE1","TEK","KDR","MET","ADAM10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14960","full_name":"Leukocyte cell-derived chemotaxin-2","aliases":[],"length_aa":151,"mass_kda":16.4,"function":"Has a neutrophil chemotactic activity. Also a positive regulator of chondrocyte proliferation (PubMed:9524238). 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developmental stages by activating the ADAM10-NOTCH signaling pathway.","date":"2025","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/41811354","citation_count":1,"is_preprint":false},{"pmid":"35986199","id":"PMC_35986199","title":"Bystander LECT2 amyloidosis in tumor nephrectomy.","date":"2022","source":"CEN case reports","url":"https://pubmed.ncbi.nlm.nih.gov/35986199","citation_count":1,"is_preprint":false},{"pmid":"29845097","id":"PMC_29845097","title":"Data on functional characterization of LECT2 from Lampetra japonica.","date":"2018","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/29845097","citation_count":1,"is_preprint":false},{"pmid":"36798409","id":"PMC_36798409","title":"Cryo-EM Structure of a Human LECT2 Amyloid Fibril Reveals a Network of Polar Ladders at its Core.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36798409","citation_count":1,"is_preprint":false},{"pmid":"40398731","id":"PMC_40398731","title":"The role of LECT2 in kidney fibrosis progression and endoplasmic reticulum stress.","date":"2025","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40398731","citation_count":0,"is_preprint":false},{"pmid":"39957753","id":"PMC_39957753","title":"Leukocyte cell-derived chemotaxin 2 (LECT2) regulates liver ischemia-reperfusion injury.","date":"2024","source":"Liver research (Beijing, China)","url":"https://pubmed.ncbi.nlm.nih.gov/39957753","citation_count":0,"is_preprint":false},{"pmid":"41185854","id":"PMC_41185854","title":"Elevated LECT2 and PEDF in Pediatric MAFLD: Diagnostic Performance and Metabolic Correlations.","date":"2025","source":"Diabetes, metabolic syndrome and obesity : targets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41185854","citation_count":0,"is_preprint":false},{"pmid":"37503176","id":"PMC_37503176","title":"Mimicking Kidney Flow Shear Efficiently Induces Aggregation of LECT2, a Protein Involved in Renal Amyloidosis.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/37503176","citation_count":0,"is_preprint":false},{"pmid":"23389976","id":"PMC_23389976","title":"[Yeast-based production, purification and bioactivity assay of rainbow trout LECT2].","date":"2013","source":"Dong wu xue yan jiu = Zoological research","url":"https://pubmed.ncbi.nlm.nih.gov/23389976","citation_count":0,"is_preprint":false},{"pmid":"41826410","id":"PMC_41826410","title":"ITPR3 promotes liver fibrosis by damaging hepatocytes via the Ca2+/NF-B/LECT2 pathway.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41826410","citation_count":0,"is_preprint":false},{"pmid":"42044766","id":"PMC_42044766","title":"LS21013A-06, a PDE4 inhibitor, preserves blood-brain barrier integrity in experimental ischemic stroke models through PKA-dependent modulation of LECT2.","date":"2026","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/42044766","citation_count":0,"is_preprint":false},{"pmid":"42235328","id":"PMC_42235328","title":"Hepatic Senp2 deletion resolves the angiogenic switch in fibrosis via β-catenin/LECT2.","date":"2026","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/42235328","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.15.664973","title":"Structural polymorphism of  <i>ex-vivo</i>  ALECT2 amyloid fibrils revealed by cryo-EM","date":"2025-07-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.15.664973","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.13.24315422","title":"Discovery of novel obesity genes through cross-ancestry analysis","date":"2024-10-16","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.13.24315422","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":44884,"output_tokens":7186,"usd":0.121221,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16361,"output_tokens":5366,"usd":0.107978,"stage2_stop_reason":"end_turn"},"total_usd":0.229199,"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\": 1996,\n      \"finding\": \"LECT2 was purified from culture fluid of PHA-activated human T-cell leukemia SKW-3 cells as a 16-kDa basic protein with neutrophil chemotactic activity, establishing it as a novel chemotactic factor distinct from all previously known chemotactic factors.\",\n      \"method\": \"Protein purification, SDS-PAGE, amino acid sequence analysis, neutrophil chemotaxis assay\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct biochemical purification and in vitro activity assay, single lab, single study\",\n      \"pmids\": [\"8877413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Recombinant LECT2 produced in CHO and L929 cells is a secreted 16-kDa protein expressed in hepatocytes; immunostaining demonstrated diffuse cytoplasmic LECT2 in human hepatocytes, and five of six hepatoma cell lines secreted LECT2 into culture fluids.\",\n      \"method\": \"Stable transfection, recombinant protein production, ELISA, immunostaining with polyclonal and monoclonal antibodies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by immunostaining and secretion quantified by sandwich ELISA, single lab\",\n      \"pmids\": [\"9266841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"LECT2 is encoded by a ~8 kb gene with four exons and three introns, mapped to human chromosome 5q31.1-q32 by FISH; liver-specific expression is driven by transcriptional control sequences in the 5' untranslated region.\",\n      \"method\": \"Gene cloning, primer extension, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct genomic characterization and chromosomal mapping, single lab\",\n      \"pmids\": [\"9545637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LECT2 is a 133-amino-acid protein with three intramolecular disulfide bonds; properly refolded recombinant LECT2 from E. coli retains the same tertiary structure as CHO-cell-produced authentic LECT2, confirmed by CD and NMR spectroscopy.\",\n      \"method\": \"Recombinant protein expression and oxidative refolding, CD spectroscopy, NMR spectroscopy, chemotaxis assay\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structural characterization with functional validation (chemotaxis), single lab\",\n      \"pmids\": [\"12597887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LECT2 activates macrophages (but not polymorphonuclear neutrophils) via the CD209a receptor to enhance phagocytosis, bacterial killing, and gene expression changes; CD209a was identified as a specific binding partner for LECT2 and CD209a-expressing macrophages mediated protection against bacterial sepsis in vivo.\",\n      \"method\": \"Receptor identification by specific interaction assay, in vitro macrophage activation assays (phagocytosis, bacterial killing), in vivo sepsis mouse model with CD209a-expressing macrophage depletion\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor identified by specific interaction, confirmed with in vitro functional assays and in vivo epistasis (macrophage depletion), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23254286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LECT2 functions as a hepatokine linking obesity to skeletal muscle insulin resistance: LECT2 expression is negatively regulated by the energy-sensing kinase AMPK in hepatocytes; recombinant LECT2 impairs insulin signaling in C2C12 myocytes via JNK phosphorylation; genetic deletion of LECT2 in mice increases skeletal muscle insulin sensitivity.\",\n      \"method\": \"Recombinant protein treatment of myocytes (Western blot for JNK phosphorylation), LECT2 knockout mice (insulin sensitivity measurement), AMPK manipulation in HepG2/H4IIEC hepatocytes\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype plus in vitro mechanistic signaling assay plus in vivo correlation, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24478397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LECT2 induces inflammatory responses in human endothelial cells and THP-1 cells via CD209 receptor-mediated JNK phosphorylation, increasing ICAM-1, TNFα, MCP-1, and IL-1β expression and enhancing monocyte adhesion to endothelial cells; CD209 siRNA knockdown abolished these effects.\",\n      \"method\": \"Recombinant LECT2 treatment of HUVECs and THP-1 cells, Western blot, qPCR, siRNA knockdown of CD209, JNK inhibitor experiments, monocyte adhesion assay\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor knockdown with siRNA confirmed signaling dependence, multiple readouts, single lab\",\n      \"pmids\": [\"26123523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LECT2 increases mTOR phosphorylation and SREBP-1 cleavage in HepG2 cells via JNK signaling, promoting lipid accumulation and insulin resistance; gemigliptin (DPP-4 inhibitor) reduces LECT2 expression via AMPK-dependent and JNK-dependent mechanisms.\",\n      \"method\": \"Western blot for signaling pathway components in HepG2 cells, LECT2 knockdown, JNK inhibitor and AMPK inhibitor treatments, in vivo high-fat diet mouse model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling pathway interventions (inhibitors, KD) with consistent results, single lab\",\n      \"pmids\": [\"26297911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of human LECT2 reveals an M23 metalloendopeptidase fold with conserved Zn(II) coordination but lacking a catalytic histidine residue; the potential substrate-binding groove is blocked by an N-terminal intrachain loop; LECT2 is catalytically inactive as a metalloendopeptidase. Surface plasmon resonance showed LECT2 binds the c-Met receptor with micromolar affinity.\",\n      \"method\": \"X-ray crystallography (1.94 Å resolution), peptidase activity assay against multiple peptide sequences including pentaglycine, surface plasmon resonance (SPR)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determination plus enzymatic assay confirming catalytic inactivity plus SPR binding measurement, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"27334921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LECT2 drives haematopoietic stem cell (HSC) expansion in bone marrow and mobilization to blood via CD209a receptor; this effect requires macrophages and osteolineage cells and is mediated through reduction of TNF expression in these cells (demonstrated by loss of effect in TNF-KO mice).\",\n      \"method\": \"Recombinant LECT2 administration in mice, HSC quantification by flow cytometry, specific macrophage depletion, TNF knockout mice, CD209a receptor mediation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo epistasis experiments (macrophage depletion, TNF KO, CD209a receptor), consistent results across methods\",\n      \"pmids\": [\"27596364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LECT2 suppresses VEGF165-induced endothelial cell proliferation, migration, and tube formation by directly binding VEGFR2 and reducing VEGFR2 tyrosine phosphorylation and downstream ERK/AKT phosphorylation, thereby inhibiting angiogenesis in HCC.\",\n      \"method\": \"Recombinant LECT2 treatment of endothelial cells, VEGFR2 phosphorylation assay (Western blot), in vitro angiogenesis assays (proliferation, migration, tube formation), in vivo HCC xenograft model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding to VEGFR2 implied by reduced phosphorylation, multiple functional assays, single lab\",\n      \"pmids\": [\"27507763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LECT2 macrophage activation via a C-type lectin receptor (PaCLR/CD209a homolog in ayu fish) is mediated through NF-κB activation via Raf-1; CD209a Ser28 phosphorylation in the intracellular domain is required for LECT2-induced Raf-1 and NF-κB activation in macrophages.\",\n      \"method\": \"Anti-receptor neutralization, western blot for signaling components, transfection experiments, phosphorylation-site specific antibodies\",\n      \"journal\": \"Genetics and molecular research / Fish & shellfish immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific phosphorylation site identified with functional consequences, receptor neutralization confirmed pathway, single lab\",\n      \"pmids\": [\"27813598\", \"26876329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LECT2 promotes inflammation and insulin resistance in adipocytes via a CD209/P38-dependent pathway; LECT2 activates P38 phosphorylation, NF-κB/IκB phosphorylation, and IL-6 expression, impairs insulin signaling (reduced IRS-1 and Akt phosphorylation), reduces glucose uptake, and augments lipid accumulation via SREBP1c. All effects were abrogated by P38 siRNA or CD209 siRNA.\",\n      \"method\": \"Recombinant LECT2 treatment of differentiated 3T3-L1 cells, siRNA knockdown of P38 and CD209, Western blot, glucose uptake assay\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor and signaling pathway confirmed by siRNA knockdown with multiple functional readouts, single lab\",\n      \"pmids\": [\"29650721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LECT2 is a functional ligand for the endothelial receptor Tie1; LECT2 binding to Tie1 disrupts Tie1/Tie2 heterodimerization, promotes Tie2/Tie2 homodimerization, activates PPAR signaling, and inhibits endothelial cell migration and tube formation. In vivo, LECT2 overexpression inhibits portal angiogenesis and promotes sinusoid capillarization, worsening liver fibrosis; Lect2-KO mice showed reversal of these effects; AAV9-LECT2-shRNA treatment attenuated fibrosis.\",\n      \"method\": \"Ligand-receptor binding assay, Co-immunoprecipitation (Tie1/Tie2 dimerization), endothelial cell functional assays (migration, tube formation), Lect2-KO mice, AAV-shRNA in vivo knockdown, PPAR signaling assay\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — receptor identification by binding and co-IP, multiple in vitro functional assays, Lect2-KO rescue, and in vivo therapeutic intervention, multiple orthogonal methods\",\n      \"pmids\": [\"31474362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of LECT2 in MSCs activates the Wnt/β-catenin pathway and promotes osteogenic differentiation; LECT2 expression is decreased during osteogenic differentiation of MSCs, and its downregulation facilitates osteoblast differentiation.\",\n      \"method\": \"LECT2 knockdown in MSCs, Wnt/β-catenin pathway activation assay, osteogenic differentiation assay\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (KD with pathway assay), single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"32763823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of bound zinc (Zn2+) is obligatory for LECT2 fibril formation in vitro; zinc-binding affinity is strongly pH-dependent (9-13% zinc-free under normal blood pH, rising to 80% at pH 6.5). The I40V mutation does not alter zinc-binding affinity but destabilizes the zinc-free conformation. These findings suggest a mechanism where zinc loss combined with I40V mutation promotes ALECT2 amyloidosis.\",\n      \"method\": \"Electron microscopy, X-ray diffraction, NMR, fluorescence spectroscopy, zinc-binding affinity measurements, pH-dependent fibril formation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro fibril formation with multiple structural methods (EM, X-ray diffraction, NMR, fluorescence), mechanistic dissection of zinc dependence and I40V mutation effects\",\n      \"pmids\": [\"33617884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LECT2 selectively enhances LPS-induced JNK phosphorylation (but not ERK or p38) in Kupffer cells by potentiating upstream MKK4 and TAB2 phosphorylation, shifting liver macrophages to an M1-like phenotype and contributing to NASH-associated liver inflammation.\",\n      \"method\": \"LECT2 KO mice (flow cytometry for M1/M2 macrophage ratios, inflammatory cytokine mRNA), in vitro KUP5 cell signaling (Western blot for JNK, ERK, p38, MKK4, TAB2 phosphorylation), human liver biopsy correlation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse phenotype plus specific in vitro signaling pathway dissection, single lab, multiple methods\",\n      \"pmids\": [\"33436955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ER stress increases LECT2 expression in hepatocytes via the ATF4 transcription factor; ChIP assay demonstrated ATF4 directly binds three putative binding sites on the LECT2 promoter, and binding is promoted by ER stress inducers. ATF4 knockdown suppressed ER stress-induced LECT2 expression; ATF4 overexpression enhanced it.\",\n      \"method\": \"ER stress induction in HepG2 cells, siRNA knockdown of UPR pathway genes, ATF4 overexpression, ChIP-qPCR assay, in vivo obese mouse liver expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR directly demonstrated ATF4 binding to LECT2 promoter, corroborated by KD/OE experiments, single lab\",\n      \"pmids\": [\"34808500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LECT2 ameliorates hyperglycemia-induced blood-retinal barrier impairment by activating the Tie2/Akt/mTOR signaling pathway, increasing interendothelial tight junction proteins (ZO1, VE-cadherin, occludin) and attenuating endothelial cell permeability, migration, and tube formation.\",\n      \"method\": \"Recombinant LECT2 treatment of HRMECs and HUVECs under high-glucose conditions, Western blot for Tie2/Akt/mTOR pathway and junction proteins, FITC-dextran permeability assay, intravitreal injection in streptozotocin-induced diabetic mice, electron microscopy\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro signaling pathway with multiple junction protein readouts confirmed in vivo by intravitreal injection, single lab\",\n      \"pmids\": [\"35262733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of recombinant human LECT2 amyloid fibrils reveals two mating protofilaments with ordered core spanning residues 55-75 of the LECT2 sequence; the fibril core is stabilized by hydrophobic contacts and hydrogen-bonded uncharged polar residues, and fibrils are resistant to 3M urea and proteinase K.\",\n      \"method\": \"Single-particle cryo-EM, protease/denaturant resistance assays\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure determination with functional validation (denaturant and protease resistance), peer-reviewed\",\n      \"pmids\": [\"37657439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LECT2 modulates dendritic cell function during H. pylori infection via CD209a receptor; LECT2 promoted BMDC maturation and skewed cytokine production toward IL-10 (anti-inflammatory) and away from IL-23p40, shifting T-cell differentiation from Th1/Th17 toward Treg. CD209a-deficient BMDCs did not respond to LECT2. The signaling pathway involves CD209a-JNK/P38 MAPK.\",\n      \"method\": \"LECT2 treatment of bone marrow-derived DCs from WT, CD209a-KO, and LECT2-KO mice; flow cytometry; Western blot; real-time PCR; T-cell co-culture differentiation assay\",\n      \"journal\": \"Journal of gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CD209a-KO DCs confirm receptor specificity, multiple functional and signaling readouts, single lab\",\n      \"pmids\": [\"36740832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Physiological kidney-like flow shear (generated by microfluidic device with progressively narrowing channels) efficiently induces LECT2 fibril formation in combination with zinc loss; the I40V mutation accelerates fibril formation and increases aggregate size and density under flow shear conditions. Fibril morphology differs between laminar flow shear and shaking/stirring.\",\n      \"method\": \"Microfluidic device mimicking renal flow shear, electron microscopy of resulting fibrils, comparison of WT vs I40V LECT2 fibrillation kinetics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro fibrillation under physiological shear conditions with EM characterization; I40V mutation effect demonstrated directly, single lab\",\n      \"pmids\": [\"38537700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LECT2 promotes liver regeneration by activating the ADAM10-NOTCH signaling pathway; hepatocyte-specific Lect2-KO impairs liver regeneration after partial hepatectomy across multiple age groups, and ADAM10 suppression abolishes the pro-regenerative effect of LECT2 overexpression. AAV-mediated Lect2 overexpression enhanced post-hepatectomy regenerative capacity.\",\n      \"method\": \"RNA-seq, scRNA-seq, hepatocyte-specific Lect2-KO mice, co-immunoprecipitation, ADAM10 inhibition experiments, AAV-mediated Lect2 overexpression, Ki-67/PCNA staining\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via ADAM10 inhibition rescuing Lect2-OE, KO mice phenotype, co-IP showing pathway interaction, single lab\",\n      \"pmids\": [\"41811354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LPS directly induces LECT2 expression in hepatocytes via TLR4 receptor signaling; downstream p38 MAPK activates AP-1 (c-Fos/c-Jun), which directly binds a putative AP-1-like site on the Lect2 promoter as confirmed by ChIP-qPCR, driving LECT2 transcription during inflammation.\",\n      \"method\": \"TLR4-specific inhibitor, p38 MAPK inhibitor/agonist, c-Fos/c-Jun overexpression, ChIP-qPCR, Lect2 promoter analysis in AML12 hepatocytes\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR confirmed direct AP-1 binding to Lect2 promoter, pharmacological pathway confirmation, single lab\",\n      \"pmids\": [\"40495481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Ex-vivo ALECT2 amyloid fibrils extracted from a patient kidney show structural polymorphism: a predominant single-protofilament morphology comprising full-length 133-residue LECT2 retaining all three native disulfide bonds, and two minor double-protofilament morphologies with similar fold but different inter-filament interfaces. Mass spectrometry revealed acetylation within fibrils.\",\n      \"method\": \"Cryo-EM of ex-vivo patient-derived fibrils, mass spectrometry\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — cryo-EM structure of ex-vivo fibrils with MS validation, but preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.07.15.664973\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LECT2 regulates axon and dendrite extension in hippocampal neurons; neurons from LECT2-KO mice showed significantly shorter axons and dendrites than wild-type, and displayed altered expression of neurotrophins NGF, BDNF, and NT-3 during neuronal development.\",\n      \"method\": \"LECT2-KO mouse hippocampal neuron culture, morphometric analysis of neurite extension, neurotrophin expression analysis\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO mouse with defined morphological phenotype and expression readouts, single lab, single study\",\n      \"pmids\": [\"19917270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LECT2 regulates neuritic extension through control of microtubule morphology by modulating katanin-P60 levels; LECT2-KO hippocampal neurons showed fragmented, shorter microtubules and elevated katanin-P60 expression compared to wild-type neurons.\",\n      \"method\": \"LECT2-KO mouse hippocampal neuron culture, microtubule morphology analysis, Western blot for katanin-P60 expression\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KO comparison with protein expression readout, no direct rescue or mechanistic intervention, single lab\",\n      \"pmids\": [\"20463617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LECT2 overexpression in endothelial cells promotes kidney fibrosis via activation of the EGFR/AKT/PI3K pathway; Lect2-KO mice showed reduced fibrosis, reduced myofibroblast activation, and less collagen deposition in a kidney fibrosis model, with increased CHOP expression and earlier endothelial cell activation.\",\n      \"method\": \"Lect2-KO mice kidney fibrosis model, LECT2 overexpression in EA.hy926 cells, Western blot for EGFR/AKT/PI3K pathway, histological analysis, Lect2 reporter mice\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice and OE cell experiments with defined signaling pathway, multiple histological readouts, single lab\",\n      \"pmids\": [\"40398731\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LECT2 is a 16-kDa liver-derived secreted protein (hepatokine) that functions as a pleiotropic ligand for multiple cell-surface receptors—including Tie1 (on endothelial cells), CD209/CD209a (on macrophages and immune cells), VEGFR2, and c-Met—adopting a catalytically inactive M23 metalloendopeptidase fold that coordinates a single Zn2+ ion; receptor binding activates downstream signaling cascades (JNK, p38 MAPK, NF-κB, PPAR, Tie2/Akt/mTOR, ADAM10-NOTCH) that regulate neutrophil chemotaxis, macrophage activation and polarization, endothelial cell migration and angiogenesis, skeletal muscle insulin resistance, liver fibrosis, liver regeneration, HSC homeostasis, and neuronal morphology, while loss of its bound zinc together with the I40V polymorphism promotes amyloid fibril formation (ALECT2 amyloidosis) under physiological flow shear conditions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LECT2 is a liver-derived, 16-kDa secreted protein (hepatokine) that functions as a pleiotropic ligand for cell-surface receptors, transducing metabolic and inflammatory cues into signaling across immune, endothelial, hepatic, and neuronal compartments [#1, #5]. Structurally it adopts an M23 metalloendopeptidase fold that coordinates a single Zn(II) ion but lacks the catalytic histidine and has a substrate groove occluded by an N-terminal loop, rendering it catalytically inactive; it engages the c-Met receptor with micromolar affinity [#8]. Through the C-type lectin receptor CD209/CD209a it activates macrophages, dendritic cells, and adipocytes via JNK, p38, and NF-\\u03baB signaling, modulating phagocytosis and bacterial killing, immune polarization, and inflammation-driven insulin resistance [#4, #12, #20]. As a metabolic effector, hepatic LECT2 is repressed by AMPK and impairs insulin signaling in skeletal muscle through JNK, with LECT2 deletion increasing muscle insulin sensitivity [#5]. On endothelium LECT2 acts as a Tie1 ligand that disrupts Tie1/Tie2 heterodimerization and drives PPAR signaling to inhibit angiogenesis and worsen liver fibrosis, while also binding VEGFR2 to suppress VEGF-driven endothelial proliferation [#10, #13]. It additionally drives haematopoietic stem cell expansion via CD209a, promotes liver regeneration through ADAM10-NOTCH signaling, and regulates hippocampal neurite extension via control of katanin-P60 and microtubule morphology [#9, #22, #25]. Hepatic LECT2 transcription is induced by ER stress through ATF4 and by LPS/TLR4-p38-AP-1 signaling [#17, #23]. Loss of bound zinc is obligatory for conversion of LECT2 into amyloid fibrils, a process accelerated by the I40V polymorphism and physiological renal flow shear and underlying ALECT2 amyloidosis [#15, #21].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established LECT2 as a novel secreted neutrophil chemotactic factor, defining it as a distinct extracellular signaling protein.\",\n      \"evidence\": \"Protein purification from PHA-activated T-cell leukemia cells with chemotaxis assay\",\n      \"pmids\": [\"8877413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor identified\", \"Mechanism of chemotaxis undefined\", \"In vitro activity only\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Identified the hepatocyte as the principal source of secreted LECT2, framing it as a liver-derived factor.\",\n      \"evidence\": \"Recombinant expression, ELISA, and immunostaining of human hepatocytes and hepatoma lines\",\n      \"pmids\": [\"9266841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of hepatic secretion not addressed\", \"Regulation of expression unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the gene structure and mapped liver-specific expression to 5' regulatory sequences, anchoring tissue-restricted control.\",\n      \"evidence\": \"Gene cloning, primer extension, and FISH mapping to chromosome 5q31.1-q32\",\n      \"pmids\": [\"9545637\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific transcription factors not identified\", \"No upstream signaling defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the disulfide-bonded folded tertiary structure of LECT2, enabling functional recombinant production.\",\n      \"evidence\": \"Oxidative refolding of E. coli protein with CD/NMR spectroscopy and chemotaxis validation\",\n      \"pmids\": [\"12597887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic-resolution fold yet\", \"Receptor engagement not structurally mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified CD209a as a specific LECT2 receptor on macrophages, establishing a defined receptor-mediated immune function with in vivo protection against sepsis.\",\n      \"evidence\": \"Receptor binding assay, macrophage phagocytosis/killing assays, and CD209a-macrophage depletion sepsis model\",\n      \"pmids\": [\"23254286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface not structurally defined\", \"Intracellular signaling steps not fully resolved at the time\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Cast LECT2 as a hepatokine linking obesity to muscle insulin resistance via AMPK-controlled expression and JNK-dependent signaling.\",\n      \"evidence\": \"LECT2-KO mice insulin sensitivity, C2C12 JNK phosphorylation, and AMPK manipulation in hepatocytes\",\n      \"pmids\": [\"24478397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Muscle receptor mediating the effect not identified\", \"Direct receptor on myocytes undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended CD209/JNK signaling to endothelial and hepatic lipogenic inflammation, mechanistically tying LECT2 to vascular inflammation and lipid accumulation.\",\n      \"evidence\": \"CD209 siRNA knockdown in HUVEC/THP-1 with JNK readouts and mTOR/SREBP-1 signaling in HepG2 cells\",\n      \"pmids\": [\"26123523\", \"26297911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CD209 binding affinity not measured\", \"Cell-type specificity of receptor usage unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Solved the crystal structure revealing a catalytically dead M23 metalloendopeptidase fold with Zn coordination and demonstrated direct c-Met binding, redefining LECT2 as a receptor ligand rather than a protease.\",\n      \"evidence\": \"1.94 \\u00c5 X-ray crystallography, peptidase assays, and SPR binding to c-Met\",\n      \"pmids\": [\"27334921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of c-Met binding not established\", \"Role of bound zinc in signaling not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated LECT2/CD209a control of HSC expansion and VEGFR2-mediated angiogenesis suppression, broadening receptor repertoire and physiological roles.\",\n      \"evidence\": \"In vivo macrophage depletion and TNF-KO HSC experiments; VEGFR2 phosphorylation assays and HCC xenografts\",\n      \"pmids\": [\"27596364\", \"27507763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct VEGFR2 binding affinity not quantified\", \"Cross-talk among multiple receptors unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped the CD209a intracellular signaling route, identifying a required Ser28 phosphorylation event upstream of Raf-1/NF-\\u03baB.\",\n      \"evidence\": \"Receptor neutralization, phospho-site antibodies, and transfection in fish/macrophage models\",\n      \"pmids\": [\"27813598\", \"26876329\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation to mammalian CD209 signaling not fully shown\", \"Kinase responsible for Ser28 phosphorylation unidentified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified Tie1 as a LECT2 receptor whose engagement shifts Tie dimerization toward Tie2 homodimers and drives PPAR signaling, mechanistically explaining LECT2-driven fibrosis and sinusoidal capillarization.\",\n      \"evidence\": \"Binding/co-IP, endothelial functional assays, Lect2-KO rescue, and AAV9-shRNA therapeutic intervention\",\n      \"pmids\": [\"31474362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Tie1 engagement undefined\", \"Hierarchy among CD209/Tie1/VEGFR2/c-Met engagement unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked LECT2 downregulation to Wnt/\\u03b2-catenin-driven osteogenic differentiation of MSCs.\",\n      \"evidence\": \"LECT2 knockdown in MSCs with Wnt pathway and osteogenic differentiation assays\",\n      \"pmids\": [\"32763823\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single method (knockdown) without rescue\", \"Receptor mediating the effect not identified\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the molecular basis of ALECT2 amyloidosis: zinc loss is obligatory for fibril formation, is pH-dependent, and the I40V mutation destabilizes the zinc-free state.\",\n      \"evidence\": \"In vitro reconstituted fibril formation with EM, X-ray diffraction, NMR, and zinc-binding measurements\",\n      \"pmids\": [\"33617884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of zinc loss in vivo not defined at the time\", \"Fibril atomic structure not yet resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined LECT2 control of liver macrophage and hepatocyte inflammatory programs, including selective JNK potentiation in Kupffer cells and ER-stress/ATF4-driven hepatic LECT2 induction.\",\n      \"evidence\": \"LECT2-KO mice, KUP5 signaling dissection, and ATF4 ChIP-qPCR with KD/OE in HepG2 cells\",\n      \"pmids\": [\"33436955\", \"34808500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating Kupffer cell signaling not pinpointed\", \"Integration of metabolic and stress inputs incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed LECT2-Tie2/Akt/mTOR signaling stabilizes endothelial barriers, demonstrating context-dependent protective endothelial outcomes.\",\n      \"evidence\": \"Recombinant LECT2 on retinal/HUVEC endothelial cells with permeability and junction protein readouts and intravitreal injection in diabetic mice\",\n      \"pmids\": [\"35262733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with anti-angiogenic Tie1 effects unresolved\", \"Direct receptor responsible in this context not formally distinguished\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the cryo-EM fibril architecture (ordered core residues 55-75) and showed CD209a-dependent dendritic cell tolerogenic skewing, advancing both the amyloid and immunomodulatory mechanisms.\",\n      \"evidence\": \"Single-particle cryo-EM of recombinant fibrils; CD209a-KO BMDC assays with T-cell differentiation readouts\",\n      \"pmids\": [\"37657439\", \"36740832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Recombinant fibril core differs from ex-vivo fibrils (later finding)\", \"Trigger converting native to fibrillar form in vivo not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that physiological renal flow shear, combined with zinc loss, efficiently nucleates LECT2 fibrils and that I40V accelerates this, linking kidney microenvironment to amyloid deposition.\",\n      \"evidence\": \"Microfluidic shear device with EM and WT vs I40V fibrillation kinetics\",\n      \"pmids\": [\"38537700\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo confirmation of shear-driven fibrillation lacking\", \"Quantitative contribution of shear vs zinc loss not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded LECT2 mechanisms to liver regeneration (ADAM10-NOTCH), kidney fibrosis (EGFR/AKT/PI3K), TLR4-p38-AP-1 transcriptional induction, and resolved an ex-vivo patient fibril structure differing from recombinant fibrils.\",\n      \"evidence\": \"Hepatocyte-specific Lect2-KO with ADAM10 inhibition and co-IP; Lect2-KO kidney fibrosis model; ChIP-qPCR of AP-1 on Lect2 promoter; cryo-EM/MS of patient-derived fibrils (one preprint)\",\n      \"pmids\": [\"41811354\", \"40398731\", \"40495481\", \"bio_10.1101_2025.07.15.664973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating ADAM10-NOTCH activation not identified\", \"Reconciliation of full-length disulfide-intact ex-vivo fibrils with the recombinant 55-75 core unresolved\", \"Kidney fibrosis receptor undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LECT2 selects among its multiple receptors (CD209/CD209a, Tie1, VEGFR2, c-Met) in a given cell type, and what physiological cue triggers in vivo zinc loss and the native-to-amyloid transition, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of any LECT2-receptor complex\", \"Receptor hierarchy/competition mechanism undefined\", \"In vivo trigger of pathological fibrillation not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4, 13, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [4, 13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 13, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 9, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5, 12, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 19, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CD209\", \"TIE1\", \"TEK\", \"KDR\", \"MET\", \"ADAM10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}