Affinage

IDE

Insulin-degrading enzyme · UniProt P14735

Round 2 corrected
Length
1019 aa
Mass
118.0 kDa
Annotated
2026-04-28
130 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IDE is a Zn2+-metalloendopeptidase that forms a dimeric degradation chamber to selectively encapsulate and cleave structurally diverse amyloidogenic and metabolic peptides—including insulin, amyloid-β (Aβ), amylin, glucagon, and the APP intracellular domain (AICD)—thereby serving as a central regulator of peptide clearance in both metabolic and neurodegenerative contexts (PMID:9830016, PMID:17051221, PMID:12634421). Crystal structures show that IDE-N and IDE-C halves enclose a size- and charge-selective chamber whose catalytic efficiency depends on oligomerization-mediated allosteric activation, with disruption of the dimer interface collapsing activity on large substrates and abolishing allosteric regulation (PMID:17051221, PMID:20300529). IDE localizes to the cytosol, detergent-resistant membrane microdomains, and the cell surface, and its expression is upregulated by insulin receptor/PI3K/Akt signaling and by sorting nexin 5 in renal proximal tubules; IDE-knockout mice exhibit hyperinsulinemia, glucose intolerance, cerebral Aβ accumulation, impaired β-cell glucose-stimulated insulin secretion, and hippocampal microgliosis (PMID:10684867, PMID:19117523, PMID:15590928, PMID:29080975, PMID:12634421, PMID:23349488, PMID:37817156). In pancreatic β-cells, IDE maintains autophagic flux and clears amyloidogenic α-synuclein to sustain releasable insulin granule pools, while in microglia it exerts a non-enzymatic role in phenotypic modulation relevant to neuroinflammation (PMID:23349488, PMID:37817156).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    Identification of IDE as the principal extracellular Aβ-degrading protease established a direct link between insulin metabolism and amyloid clearance, opening the field of IDE-mediated neuroprotection.

    Evidence Purification from microglial conditioned medium with competitive inhibition, immunodepletion, and CSF detection

    PMID:9830016

    Open questions at the time
    • Relative contribution of IDE versus other Aβ-degrading proteases (e.g., neprilysin) not delineated
    • Mechanism of IDE secretion unknown
  2. 2000 High

    Demonstration that a membrane-associated form of IDE on the neuronal cell surface degrades secreted Aβ resolved the topology paradox of how a predominantly cytosolic protease accesses extracellular substrates.

    Evidence Cell-surface biotinylation and catalytic-dead mutant (E111Q) in primary neurons and PC12 cells

    PMID:10684867

    Open questions at the time
    • Mechanism of IDE membrane association and the nature of the ~5 kDa size difference from cytosolic IDE remain uncharacterized
    • Whether membrane-associated IDE preferentially targets Aβ40 versus Aβ42 unclear
  3. 2003 High

    IDE-knockout mice provided definitive genetic proof that IDE is a major in vivo regulator of both Aβ and insulin catabolism, linking IDE deficiency to hyperinsulinemia, glucose intolerance, and cerebral Aβ accumulation.

    Evidence IDE-null mouse with ex vivo brain membrane degradation, primary neuronal cultures, and metabolic phenotyping

    PMID:12634421

    Open questions at the time
    • Relative contribution of hepatic versus neural IDE to systemic insulin clearance not resolved
    • Whether IDE degrades AICD in a physiologically rate-limiting manner in vivo unclear
  4. 2004 High

    Discovery that insulin receptor/PI3K/Akt signaling upregulates IDE expression established a negative-feedback loop coupling insulin signaling to its own degradation, with implications for insulin resistance in Alzheimer's disease.

    Evidence PI3K inhibitor treatment in primary hippocampal neurons and correlation with reduced IDE in AD brain tissue

    PMID:15590928

    Open questions at the time
    • Transcriptional versus post-translational mechanism of PI3K-dependent IDE upregulation not defined
    • Causal direction of IDE reduction in AD brain not established
  5. 2006 High

    Crystal structures of IDE bound to insulin B chain, Aβ, amylin, and glucagon revealed the enclosed degradation chamber architecture and explained substrate selectivity through size/charge complementarity and β-sheet-mediated capture.

    Evidence X-ray crystallography of four substrate-bound complexes with mutagenesis of IDE-N/IDE-C interface

    PMID:17051221

    Open questions at the time
    • Full-length insulin-bound structure not obtained
    • Structural basis for chamber opening/closing dynamics not captured
  6. 2008 High

    Localization of IDE to detergent-resistant membrane microdomains (lipid rafts) and the demonstration that raft displacement impairs Aβ and insulin degradation revealed that IDE's proteolytic function is spatially regulated by membrane cholesterol.

    Evidence Immunogold EM, sucrose gradient fractionation, MβCD treatment, and seladin-1 KO mouse validation

    PMID:19117523

    Open questions at the time
    • Direct mechanism by which IDE associates with lipid rafts (lipid modification, adaptor protein) unknown
    • Whether raft-associated IDE represents a distinct post-translationally modified pool not determined
  7. 2010 High

    Engineering a monomeric IDE variant demonstrated that dimerization is required for allosteric activation and efficient degradation of large substrates, establishing oligomerization as a critical regulatory mechanism.

    Evidence Dimer-interface deletion mutant with kinetic analysis across multiple substrates and activators

    PMID:20300529

    Open questions at the time
    • Whether physiological regulators modulate IDE oligomerization state in vivo not tested
    • Structural basis of allosteric communication between subunits unresolved
  8. 2013 High

    IDE-knockout and haploinsufficient β-cells revealed that IDE maintains glucose-stimulated insulin secretion by sustaining autophagic flux and clearing α-synuclein, linking IDE to β-cell proteostasis beyond its known catabolic role.

    Evidence IDE KO and haplo-insufficient mice, α-synuclein gain/loss-of-function in vivo, autophagy and microtubule quantification

    PMID:23349488

    Open questions at the time
    • Whether IDE degrades α-synuclein directly or acts indirectly through autophagy modulation not resolved
    • Mechanism linking IDE to microtubule maintenance unclear
  9. 2017 High

    Identification of SNX5 as a positive regulator of IDE expression and activity in renal proximal tubules extended IDE regulation beyond neurons, showing that insulin-stimulated SNX5–IDE co-localization controls renal insulin clearance.

    Evidence Reciprocal Co-IP, confocal co-localization, renal-selective siRNA knockdown in mice with metabolic phenotyping

    PMID:29080975

    Open questions at the time
    • Mechanism by which SNX5 stabilizes or promotes IDE expression not defined
    • Whether SNX5–IDE interaction is direct or mediated by a trafficking complex unknown
  10. 2019 Medium

    The finding that SIRT4 bridges PTEN to IDE for lysosomal degradation under starvation stress revealed a non-canonical IDE function in which the protease participates in targeted protein disposal through the lysosomal pathway, coupling nutrient sensing to PI3K–AKT–mTOR signaling.

    Evidence Co-IP, overexpression/knockdown, lysosome inhibitor rescue of PTEN under starvation

    PMID:30649986

    Open questions at the time
    • Whether IDE directly cleaves PTEN or acts as a scaffold/adaptor for lysosomal targeting not distinguished
    • Single-lab finding; independent replication needed
    • Whether this pathway operates in neurons or β-cells unknown
  11. 2023 Medium

    IDE knockout induces hippocampal microgliosis and impairs microglial phenotypic switching through a mechanism independent of its enzymatic activity, establishing a non-catalytic scaffolding or signaling role in neuroinflammation.

    Evidence IDE-null and haploinsufficient mice, primary microglial cultures, immunohistochemistry, and functional phenotyping

    PMID:37817156

    Open questions at the time
    • Molecular basis of IDE's non-enzymatic microglial function completely uncharacterized
    • Whether non-enzymatic role involves protein–protein interactions or structural scaffolding unknown
    • Relevance to human AD microglia not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural dynamics of IDE chamber gating in vivo, the molecular basis of its non-enzymatic functions in microglia and protein quality control, whether IDE oligomerization state is physiologically regulated, and the direct mechanism linking IDE to autophagic flux in β-cells.
  • No in vivo structure of IDE captured in open/closed transition states
  • Non-enzymatic interactome of IDE undefined
  • Relative tissue-specific contributions to systemic insulin clearance not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-1643685 Disease 3 R-HSA-162582 Signal Transduction 2 GO:0005576 extracellular region 1 R-HSA-9612973 Autophagy 1
Partners
ANT2ANT3ITM2BPTENSIRT4SNX5

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 Insulin-degrading enzyme (IDE) was purified and identified as the principal protease responsible for degrading extracellular amyloid beta-protein (Aβ) under biologically relevant conditions. IDE was found in both cytosol and released into conditioned medium by intact microglial cells, and its Aβ-degrading activity was abolished by competitive IDE substrates (insulin) and IDE inhibitors, and removed by immunodepletion with an IDE antibody. IDE activity was also associated with time-dependent oligomerization of synthetic Aβ. Protein purification, competitive inhibition assay, immunodepletion, identification of IDE in human cerebrospinal fluid The Journal of biological chemistry High 9830016
2000 In differentiated neurons, IDE localizes to the cell surface (membrane-associated form ~5 kDa larger than cytosolic form) rather than being secreted, and this membrane-associated IDE degrades extracellularly secreted Aβ. Overexpression of IDE markedly reduced steady-state extracellular Aβ(40) and Aβ(42), while a catalytic site mutation (E111Q) abolished this effect. Cell-surface biotinylation, overexpression with active-site mutagenesis, primary neuronal cultures, PC12 differentiation model The Journal of neuroscience High 10684867
2003 IDE knockout mice (IDE−/−) showed >50% decrease in Aβ degradation in brain membrane fractions and primary neuronal cultures, and a similar deficit in insulin degradation in liver, resulting in increased cerebral Aβ accumulation, hyperinsulinemia, and glucose intolerance. IDE also degrades the intracellular APP domain (AICD) released by γ-secretase in vivo. IDE knockout mouse model, primary neuronal cultures, ex vivo brain membrane degradation assays, metabolic phenotyping Proceedings of the National Academy of Sciences of the United States of America High 12634421
2004 Insulin receptor signaling via PI3 kinase/Akt upregulates IDE protein levels in primary hippocampal neurons (~25% increase with insulin treatment), establishing a negative feedback mechanism. PI3 kinase inhibitors (wortmannin, LY294002) abolished IDE upregulation. Reduced PI3K subunit P85 correlated with reduced IDE in AD brains and APP transgenic mice on a high-fat diet, with associated increases in Aβ monomer. Primary hippocampal neuron culture, PI3K inhibitor treatment, western blotting, analysis of AD brain tissue and transgenic mouse model The Journal of neuroscience High 15590928
2006 Crystal structures of human IDE in complex with four substrates (insulin B chain, Aβ1–40, amylin, glucagon) revealed that IDE-N and IDE-C domains form an enclosed substrate-degradation chamber. Substrate access requires repositioning of the domains; IDE uses size and charge distribution of the cavity for selective substrate entrapment. Substrates undergo conformational changes forming β-sheets with two discrete IDE regions. Mutations disrupting the IDE-N/IDE-C interface increased catalytic activity ~40-fold. X-ray crystallography (multiple substrate-bound structures), active-site and interface mutagenesis Nature High 17051221
2007 SIRT4, a mitochondrial ADP-ribosyltransferase, was found to co-immunoprecipitate with IDE and the ADP/ATP carrier proteins ANT2 and ANT3 in mitochondria. SIRT4 depletion in insulin-producing INS-1E cells increased glucose-stimulated insulin secretion, implicating the SIRT4–IDE interaction in regulation of insulin secretion. Co-immunoprecipitation, mass spectrometry, siRNA depletion in pancreatic beta-cell line The Journal of biological chemistry Medium 17715127
2010 Deletion of the putative dimer interface in the C-terminal region of IDE produced a monomeric variant that retained enzymatic activity but displayed Michaelis-Menten kinetics instead of allosteric behavior. Monomeric IDE retained ~25% activity on small peptide substrates but only 0.25–1% on larger substrates (β-endorphin, Aβ1–40). Neither bradykinin, dynorphin B-9, nor polyphosphates could activate the monomeric variant, demonstrating that oligomerization (predominantly dimer) is required for IDE's allosteric regulatory properties and conformational activation. Site-directed mutagenesis of dimer interface, analytical ultracentrifugation/gel filtration, enzyme kinetics with multiple substrates and activators PloS one High 20300529
2011 BRI2 (ITM2B) overexpression reduces extracellular Aβ levels by increasing secreted IDE protein. This effect was observed with both wild-type BRI2 and its disease-associated mutant ADanPP, and was retained by a BRI2 construct lacking its C-terminal 23-amino acid peptide, suggesting BRI2 acts as a receptor-like regulator of IDE secretion and thereby influences APP/Aβ metabolism. Overexpression in cell lines, IDE secretion assay (western blot of conditioned medium), Aβ ELISA, in vivo AD mouse model plaque quantification The Journal of biological chemistry Medium 21873424
2012 IDE behaves as a heat shock-like protein: normal and malignant cells exposed to various stresses (heat, oxidative, genotoxic) markedly upregulate IDE expression. In neuroblastoma cells (SHSY5Y), IDE silencing inhibits cell proliferation and triggers cell death. IDE co-immunoprecipitates with proteasome components and ubiquitin, and IDE inhibition decreases poly-ubiquitinated protein content, indicating a role for IDE in ubiquitin/proteasome-related protein quality control. Stress induction assays (heat shock, oxidative stress), IDE knockdown, cell proliferation/death assays, co-immunoprecipitation with proteasome and ubiquitin The Journal of biological chemistry Medium 23188819
2013 IDE knockout mice show decreased glucose-stimulated insulin secretion (GSIS) due to impaired replenishment of the releasable granule pool, and the Ide gene is haploinsufficient for this phenotype. IDE KO β-cells also have reduced autophagic flux and microtubule content. α-Synuclein levels are inversely correlated with IDE in β-cells of IDE KO mice and T2D patients; both gain- and loss-of-function of α-synuclein in vivo impair GSIS and autophagy, identifying IDE as a regulator of GSIS and β-cell amyloidogenic protein homeostasis. Ide knockout and haploinsufficient mouse models, GSIS assay, autophagy flux measurements, microtubule quantification, α-synuclein gain/loss-of-function in vivo Diabetes High 23349488
2008 Endogenous IDE is present in detergent-resistant membrane (DRM) microdomains (lipid rafts) in brain tissue and cultured cells, in addition to its cytosolic localization. DRM-associated IDE co-localizes with Aβ. Displacement of IDE from DRMs by methyl-β-cyclodextrin (MβCD) caused extracellular Aβ accumulation and impaired exogenous Aβ proteolysis. Mice with reduced cholesterol (seladin-1 heterozygous knockout) had less IDE in DRMs. A moderate shift of IDE from DRMs substantially decreased IDE-mediated insulin and Aβ degradation in vitro. Live immunofluorescence, immunogold electron microscopy, sucrose gradient fractionation, pulse-chase, MβCD treatment, seladin-1 KO mouse brain fractionation Molecular neurodegeneration High 19117523
2017 Renal sorting nexin 5 (SNX5) positively regulates IDE expression and activity. SNX5 co-localizes and co-immunoprecipitates with IDE at the plasma membrane and perinuclear area of human renal proximal tubule cells (hRPTCs) and in the brush border membrane of proximal tubules. Insulin increases the co-localization and co-immunoprecipitation of SNX5 and IDE. Silencing SNX5 decreases IDE expression and activity, impairs insulin/glucose responses, and increases blood insulin and glucose in mice. Spontaneously hypertensive rats have decreased renal SNX5 and IDE. Co-immunoprecipitation, confocal co-localization, siRNA knockdown in hRPTCs, renal-selective siRNA infusion in uninephrectomized mice, metabolic phenotyping Diabetologia High 29080975
2019 SIRT4 interacts with PTEN and bridges PTEN to IDE for lysosomal degradation in response to nutritional starvation stress. SIRT4 overexpression causes PTEN downregulation independently of acetylation and ubiquitination. This SIRT4–IDE–PTEN axis promotes cell survival under nutrient stress by lowering PTEN levels and thereby de-repressing the PI3K–AKT–mTOR pathway. Co-immunoprecipitation, overexpression/knockdown, lysosome inhibitor experiments, PTEN stability assays under starvation conditions FASEB journal Medium 30649986
2020 SARS-CoV-2 protein–protein interaction mapping by affinity-purification mass spectrometry identified IDE as a high-confidence interaction partner of SARS-CoV-2 Nsp2 in human cells. Affinity-purification mass spectrometry (AP-MS) in HEK293T cells expressing tagged viral proteins Nature Low 32353859
2023 IDE absence in knockout mice induces specific microgliosis in the hippocampus without astrogliosis. In primary microglial cultures, IDE absence impairs modulation of phenotypic states in response to environmental signals, with only transitory effects on Aβ management. These effects cannot be explained by IDE enzymatic activity alone, indicating a non-enzymatic role for IDE in modulating microglial function relevant to aging and Alzheimer's disease. IDE knockout mouse model (full KO and haploinsufficiency), primary microglial cultures, behavioral testing, immunohistochemistry, functional microglial phenotyping assays Journal of neuroinflammation Medium 37817156

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2007 A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2168 17293876
2007 Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science (New York, N.Y.) 1702 17463249
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2010 Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nature genetics 1401 20581827
2007 Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature genetics 1399 17192785
2003 Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proceedings of the National Academy of Sciences of the United States of America 1217 12634421
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nature genetics 834 24509480
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1998 Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. The Journal of biological chemistry 681 9830016
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2009 Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology 563 19737565
2023 Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma. The New England journal of medicine 559 36762851
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2000 Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme. The Journal of neuroscience : the official journal of the Society for Neuroscience 401 10684867
2004 14-3-3-affinity purification of over 200 human phosphoproteins reveals new links to regulation of cellular metabolism, proliferation and trafficking. The Biochemical journal 372 14744259
2007 Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. The Journal of biological chemistry 332 17715127
2019 Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer cell 298 31056398
2006 Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Nature 289 17051221
2003 Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. The American journal of pathology 287 12507914
2011 Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. Immunity 286 21903422
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2004 Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention. The Journal of neuroscience : the official journal of the Society for Neuroscience 272 15590928
2007 Common variants of the novel type 2 diabetes genes CDKAL1 and HHEX/IDE are associated with decreased pancreatic beta-cell function. Diabetes 199 17804762
2008 Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes 188 18633108
2001 The ins(ide) and out(side) of dolichyl phosphate biosynthesis and recycling in the endoplasmic reticulum. Glycobiology 150 11425794
2016 Reduction of covalently closed circular DNA with long-term nucleos(t)ide analogue treatment in chronic hepatitis B. Journal of hepatology 145 27639844
2012 Long-term continuous entecavir therapy in nucleos(t)ide-naïve chronic hepatitis B patients. Journal of hepatology 134 22659518
2013 Reduction of hepatitis B surface antigen and covalently closed circular DNA by nucleos(t)ide analogues of different potency. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 126 23376799
2012 High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 117 23137006
2016 Viral and Host Responses After Stopping Long-term Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B. The Journal of infectious diseases 113 27609808
2023 Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy. Blood cancer journal 103 37558706
2012 Clinical utility of quantitative HBsAg in natural history and nucleos(t)ide analogue treatment of chronic hepatitis B: new trick of old dog. Journal of gastroenterology 99 23090000
2013 The type 2 diabetes-associated gene ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes 87 23349488
2023 A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B. Journal of hepatology 77 37062574
2003 Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Human mutation 76 14517947
2008 Differential cerebral deposition of IDE and NEP in sporadic and familial Alzheimer's disease. Neurobiology of aging 75 19019493
2013 Ginsenoside Rg1 decreases Aβ(1-42) level by upregulating PPARγ and IDE expression in the hippocampus of a rat model of Alzheimer's disease. PloS one 71 23520555
2012 Insulin-degrading enzyme (IDE): a novel heat shock-like protein. The Journal of biological chemistry 71 23188819
2017 Relationship between HBsAg, HBcrAg and hepatocellular carcinoma in patients with undetectable HBV DNA under nucleos(t)ide therapy. Journal of viral hepatitis 68 28185363
2018 Increased NK Cell Function After Cessation of Long-Term Nucleos(t)ide Analogue Treatment in Chronic Hepatitis B Is Associated With Liver Damage and HBsAg Loss. The Journal of infectious diseases 58 29471497
2019 Finite nucleos(t)ide analog therapy in HBeAg-negative chronic hepatitis B: an emerging paradigm shift. Hepatology international 55 31559604
2004 Quantitative trait loci near the insulin-degrading enzyme (IDE) gene contribute to variation in plasma insulin levels. Diabetes 55 15277398
2020 Effect of combination treatment based on interferon and nucleos(t)ide analogues on functional cure of chronic hepatitis B: a systematic review and meta-analysis. Hepatology international 52 33185803
2021 Idecabtagene vicleucel (ide-cel) CAR T-cell therapy for relapsed and refractory multiple myeloma. Future oncology (London, England) 49 34854741
2011 Combination of hepatitis B viral antigens and DNA for prediction of relapse after discontinuation of nucleos(t)ide analogs in patients with chronic hepatitis B. Hepatology research : the official journal of the Japan Society of Hepatology 49 22103237
2022 Phase IIa, randomised, double-blind study of GSK3389404 in patients with chronic hepatitis B on stable nucleos(t)ide therapy. Journal of hepatology 46 35714812
2008 Increased expression of Abeta degrading enzyme IDE in the cortex of transgenic mice with Alzheimer's disease-like neuropathology. Neuroscience letters 45 18455870
2021 Switching to or Add-on Peginterferon in Patients on Nucleos(t)ide Analogues for Chronic Hepatitis B: The SWAP RCT. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 41 33895361
2016 The ins(ide) and outs(ide) of asymmetric stem cell division. Current opinion in cell biology 41 27318429
2015 Construction of Au-IDE/CFP10-ESAT6 aptamer/DNA-AuNPs MSPQC for rapid detection of Mycobacterium tuberculosis. Biosensors & bioelectronics 39 26513286
2013 The efficacy and safety of nucleos(t)ide analogues in the treatment of HBV-related acute-on-chronic liver failure: a meta-analysis. Annals of hepatology 38 23619252
2011 BRI2 protein regulates β-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE). The Journal of biological chemistry 38 21873424
2008 Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Abeta and insulin degradation. Molecular neurodegeneration 38 19117523
2014 Reactivation of hepatitis B virus in hematopoietic stem cell transplant recipients in Japan: efficacy of nucleos(t)ide analogues for prevention and treatment. International journal of molecular sciences 37 25421241
2017 Potential use of serum HBV RNA in antiviral therapy for chronic hepatitis B in the era of nucleos(t)ide analogs. Frontiers of medicine 36 29170915
2024 JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analogue-suppressed patients with chronic hepatitis B: REEF-2. Journal of hepatology 35 38583491
2023 Real-life experiences with CAR T-cell therapy with idecabtagene vicleucel (ide-cel) for triple-class exposed relapsed/refractory multiple myeloma patients. BMC cancer 35 37061680
2019 SIRT4 regulates PTEN stability through IDE in response to cellular stresses. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 30649986
2019 Dietary curcumin enhances insulin clearance in diet-induced obese mice via regulation of hepatic PI3K-AKT axis and IDE, and preservation of islet integrity. Nutrition & metabolism 32 31372175
2009 Combined risk effects of IDE and NEP gene variants on Alzheimer disease. Journal of neurology, neurosurgery, and psychiatry 32 19864659
2018 Stopping long-term treatment with nucleos(t)ide analogues is a favourable option for selected patients with HBeAg-negative chronic hepatitis B. Liver international : official journal of the International Association for the Study of the Liver 31 29427489
2017 Comparison of the efficacy and safety of entecavir and tenofovir in nucleos(t)ide analogue-naive chronic hepatitis B patients with high viraemia: a retrospective cohort study. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases 31 28189857
2022 Association of Serum Hepatitis B Virus RNA With Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Under Nucleos(t)ide Analogues Therapy. The Journal of infectious diseases 30 34931674
2021 Risks and Benefits of Discontinuation of Nucleos(t)ide Analogue Treatment: A Treatment Concept for Patients With HBeAg-Negative Chronic Hepatitis B. Hepatology communications 30 34558833
2020 Discontinuation of nucleos(t)ide analogues is not associated with a higher risk of HBsAg seroreversion after antiviral-induced HBsAg seroclearance: a nationwide multicentre study. Gut 30 32209606
2020 Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B. Antiviral research 30 33279523
2024 EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma. Journal for immunotherapy of cancer 29 39379098
2023 Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer's disease and brain aging. Journal of neuroinflammation 29 37817156
2019 Comparative efficacy of tenofovir and entecavir in nucleos(t)ide analogue-naive chronic hepatitis B: A systematic review and meta-analysis. PloS one 29 31751366
2018 Nucleic acid polymer REP 2139 and nucleos(T)ide analogues act synergistically against chronic hepadnaviral infection in vivo in Pekin ducks. Hepatology (Baltimore, Md.) 29 29251788
2025 ACURATE neo2 valve versus commercially available transcatheter heart valves in patients with severe aortic stenosis (ACURATE IDE): a multicentre, randomised, controlled, non-inferiority trial. Lancet (London, England) 28 40412426
2021 HBeAg-positive patients with HBsAg  < 100 IU/mL and negative HBV RNA have lower risk of virological relapse after nucleos(t)ide analogues cessation. Journal of gastroenterology 28 34292372
2012 Discrepancy of potential antiviral resistance mutation profiles within the HBV reverse transcriptase between nucleos(t)ide analogue-untreated and -treated patients with chronic hepatitis B in a hospital in China. Journal of medical virology 28 22170539
2010 A monomeric variant of insulin degrading enzyme (IDE) loses its regulatory properties. PloS one 28 20300529
2008 Nucleos(t)ide analogues for hepatitis B virus: strategies for long-term success. Best practice & research. Clinical gastroenterology 28 19187868
2018 Gemcitabine and Nucleos(t)ide Synthesis Inhibitors Are Broad-Spectrum Antiviral Drugs that Activate Innate Immunity. Viruses 27 29677162
2020 Factors associated with the biphasic kinetics of serum HBV RNA in patients with HBeAg-positive chronic hepatitis B treated with nucleos(t)ide analogues. Alimentary pharmacology & therapeutics 25 32613672
2019 Selected nucleos(t)ide-based prescribed drugs and their multi-target activity. European journal of pharmacology 24 31634460
2022 Impact of preexisting nucleos(t)ide reverse transcriptase inhibitor resistance on the effectiveness of bictegravir/emtricitabine/tenofovir alafenamide in treatment experience patients. AIDS (London, England) 23 35848506
2020 Serum Hepatitis B Virus RNA Levels Predict HBeAg Seroconversion and Virological Response in Chronic Hepatitis B Patients with High Viral Load Treated with Nucleos(t)ide Analog. Infection and drug resistance 22 32606837
2022 Ginsenoside F1 Protects the Brain against Amyloid Beta-Induced Toxicity by Regulating IDE and NEP. Life (Basel, Switzerland) 21 35054451
2013 Snapshot on drug-resistance rate and profiles in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice. Journal of medical virology 21 23588725
2013 Mutations in HBV DNA polymerase associated with nucleos(t)ide resistance are rare in treatment-naive patients. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 21 24342744
2012 Diagnostic and therapeutic progress of multi-drug resistance with anti-HBV nucleos(t)ide analogues. World journal of gastroenterology 21 23326119
2023 Antiviral activities of two nucleos(t)ide analogs against vaccinia, mpox, and cowpox viruses in primary human fibroblasts. Antiviral research 20 37270160
2021 Circulating Pregenomic Hepatitis B Virus RNA Is Primarily Full-length in Chronic Hepatitis B Patients Undergoing Nucleos(t)ide Analogue Therapy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20 32687164
2021 Resequencing and SNP discovery of Amur ide (Leuciscus waleckii) provides insights into local adaptations to extreme environments. Scientific reports 20 33658614
2017 Loss of renal SNX5 results in impaired IDE activity and insulin resistance in mice. Diabetologia 19 29080975
2023 Phase 2 results of idecabtagene vicleucel (ide-cel, bb2121) in Japanese patients with relapsed and refractory multiple myeloma. International journal of hematology 18 36690910
2020 Serum HBV RNA Dynamic and Drug Withdrawal Predictor Value in Patients With Chronic HBV Infection on Long-term Nucleos(t)ide Analogue (NA) Therapy. Journal of clinical gastroenterology 18 32604147
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