{"gene":"NAMPT","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2006,"finding":"Crystal structure of Nampt reveals it is a dimeric type II phosphoribosyltransferase; the structure in the presence and absence of NMN provides insights into the enzymatic mechanism of NMN synthesis from nicotinamide.","method":"X-ray crystallography (crystal structure determination with and without NMN product)","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with and without substrate/product, directly establishing enzyme class and catalytic mechanism","pmids":["16783373"],"is_preprint":false},{"year":2007,"finding":"Intracellular NAMPT (iNampt) is an essential NAD biosynthetic enzyme; haplodeficiency or chemical inhibition causes defects in NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic islets, correctable by NMN supplementation. Extracellular NAMPT (eNampt) does not exert insulin-mimetic effects but exhibits robust NAD biosynthetic activity.","method":"Genetic haplodeficiency mouse model, chemical inhibition, in vitro and in vivo glucose-stimulated insulin secretion assays, NMN rescue experiments, plasma NMN measurement","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, pharmacological inhibition, rescue with enzymatic product) in vivo and in vitro, replicated across conditions","pmids":["17983582"],"is_preprint":false},{"year":2007,"finding":"NAMPT is the rate-limiting enzyme that converts nicotinamide to nicotinamide mononucleotide (NMN) in the mammalian NAD biosynthetic salvage pathway from nicotinamide.","method":"Enzymatic activity assay, genetic and pharmacological perturbation of NAD biosynthesis","journal":"Current opinion in gastroenterology","confidence":"High","confidence_rationale":"Tier 1 / Strong — established by direct enzymatic assays across multiple independent studies","pmids":["17268245","17983582","16783373"],"is_preprint":false},{"year":2009,"finding":"Human hepatocytes constitutively release NAMPT into the extracellular space in a time-dependent manner; secreted NAMPT is primarily dimeric and exhibits in vitro NAD biosynthetic enzymatic activity comparable to intracellular NAMPT.","method":"Size exclusion chromatography, enzymatic activity assay, cell culture secretion experiments with HepG2 and primary human hepatocytes","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity confirmed on secreted protein with two cell models; single lab","pmids":["19912992"],"is_preprint":false},{"year":2008,"finding":"NAMPT (PBEF) interacts with NADH dehydrogenase subunit 1 (ND1), ferritin light chain, and IFITM3 in human pulmonary vascular endothelial cells; PBEF overexpression increases these interactions and intracellular oxidative stress, attenuatable by rotenone.","method":"Protein interaction identification and validation (co-immunoprecipitation/pulldown), overexpression, rotenone inhibition, computational interaction modeling","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, validated by pulldown and modeling, but mechanism of interaction not fully resolved","pmids":["18486613"],"is_preprint":false},{"year":2008,"finding":"NAMPT (PBEF) overexpression augments IL-8 secretion and IL-1β-mediated cell permeability in pulmonary vascular endothelial and epithelial cells; knockdown of PBEF inhibits IL-1β-stimulated IL-8 secretion and reduces cell permeability, establishing PBEF as a regulator of pulmonary inflammation and permeability.","method":"PBEF overexpression and siRNA knockdown in A549 and HPAEC cells, cytokine secretion assay, permeability assay","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined cellular phenotype readouts; single lab","pmids":["18996492"],"is_preprint":false},{"year":2011,"finding":"Extracellular NAMPT (visfatin) induces EMMPRIN and MMP-9 expression in macrophages via NAMPT enzymatic activity (NMN production) activating the MAPK (p38, ERK1/2)–NF-κB signaling pathway; this pro-inflammatory action is not prevented by insulin receptor blockade.","method":"Pharmacological inhibition (FK866, p38 inhibitor, ERK1/2 inhibitor, NF-κB inhibitor), exogenous NMN supplementation, RT-PCR, western blotting, gelatin zymography, THP-1 macrophage cell line","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors used orthogonally; NMN mimicry confirms enzymatic mechanism; single lab","pmids":["21327328"],"is_preprint":false},{"year":2013,"finding":"NAMPT (PBEF1) enzymatic activity is required for myeloma cell growth and osteoclast activity; inhibition by APO866 depletes NAD+, reduces PARP-1 and SIRT-1 activity, and induces apoptosis; effects are rescued by extracellular NAD+ or nicotinamide supplementation. PBEF1 knockdown phenocopies APO866 inhibition.","method":"APO866 pharmacological inhibition, PBEF1 siRNA knockdown, NAD+ rescue, PARP-1/SIRT-1 activity assays, SCID-rab in vivo xenograft model","journal":"Experimental hematology","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological and genetic inhibition with NAD+ rescue confirming on-target mechanism; in vivo validation","pmids":["23435312"],"is_preprint":false},{"year":2013,"finding":"Human islets secrete enzymatically active eNAMPT in a glucose-dependent manner requiring membrane depolarization; glucose (20 mM) increases both eNAMPT secretion and NAMPT mRNA levels; secretion is attenuated by diazoxide and nifedipine (membrane depolarization inhibitors).","method":"Static glucose-stimulated insulin secretion assay, ELISA, enzymatic activity assay on secreted NAMPT, pharmacological inhibitors (diazoxide, nifedipine), qRT-PCR, immunofluorescence/confocal imaging","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity confirmed on secreted protein; secretion mechanism dissected with specific inhibitors; single lab","pmids":["23536823"],"is_preprint":false},{"year":2014,"finding":"Visfatin/Nampt is present in human OA joint tissues in a homodimeric, enzymatically active conformation; inhibition of Nampt enzymatic activity by APO866 reduces pro-inflammatory cytokine (IL-6, KC, MCP-1) mRNA and protein expression in chondrocytes and osteoblasts, demonstrating that the pro-inflammatory action of visfatin requires its enzymatic (NAMPT) activity.","method":"Western blot, ELISA, size exclusion chromatography, colorimetric enzymatic activity assay, APO866 pharmacological inhibition, RT-PCR, primary murine chondrocyte and osteoblast cultures","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity confirmed ex vivo and in vitro; APO866 inhibition links enzymatic activity to pro-inflammatory effects; single lab","pmids":["24479481"],"is_preprint":false},{"year":2015,"finding":"Extracellular NAMPT/PBEF directly ligates Toll-like receptor 4 (TLR4) to induce NF-κB transcriptional activity and inflammatory lung injury; computational analysis shows NAMPT shares ~30% sequence identity and structural similarity with TLR4-binding protein MD-2; unlike MD-2, NAMPT alone produces robust TLR4 activation, likely via a protruding region (S402-N412) with structural similarity to LPS.","method":"Computational structural analysis, TLR4 signaling reporter assays, NF-κB transcriptional activity assays, VILI mouse model with reduced NAMPT bioavailability","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct TLR4 ligation supported by computational structural evidence and functional signaling assays; single lab, mechanism partially inferred computationally","pmids":["26272519"],"is_preprint":false},{"year":2012,"finding":"Visfatin/PBEF induces high amounts of chemokines (IL-8, MCP-1), IL-6, and MMP-3 in rheumatoid arthritis synovial fibroblasts (RASFs) through p38 MAPK phosphorylation; p38 MAPK inhibition strongly reduces these effects; visfatin/PBEF also increases directed and general fibroblast motility.","method":"Affymetrix array, RT-PCR, immunoassay, p38 MAPK inhibitor, primary RASF cultures, migration assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibitor confirms p38 MAPK involvement; multiple readouts; single lab","pmids":["22767598"],"is_preprint":false},{"year":2012,"finding":"NAMPT pathway controls GADD45A expression via FOXO3a acetylation: NAMPT overexpression decreases GADD45A expression while FK866 inhibition of NAMPT increases it; increased GADD45A expression under NAMPT inhibition involves FOXO3a acetylation (mediated through reduced SIRT1 activity).","method":"NAMPT overexpression, FK866 inhibition, SIRT1 shRNA knockdown, gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent pharmacological and genetic approaches linking NAMPT/NAD+/SIRT1 to FOXO3a acetylation and GADD45A; single lab","pmids":["22430142"],"is_preprint":false},{"year":2021,"finding":"Macrophage-derived NAMPT is required for muscle satellite cell (stem cell) proliferation after injury; specific 'dwelling' macrophages secrete NAMPT, which acts through the C-C motif chemokine receptor type 5 (Ccr5) expressed on muscle stem cells to stimulate proliferation.","method":"Zebrafish muscle injury models, live imaging of cell interactions, single-cell transcriptomics, genetic/pharmacological perturbation of NAMPT secretion","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo live imaging, genetic perturbations, single-cell profiling, receptor identification across multiple experiments","pmids":["33568815"],"is_preprint":false},{"year":2021,"finding":"STAT1 occupies a conserved enhancer element (NRE1) in intron 1 of Nampt in response to IFN-γ, driving Nampt expression; disruption of NRE1 reduces a subset of M1 macrophage genes sensitive to NAMPT activity through glycolytic processes; NRE1 deletion in macrophage lineages reduces anti-tumor immunity and increases tumor burden.","method":"ChIP-seq (STAT1 occupancy at NRE1), NRE1 mouse knockout strain, pharmacological NAMPT inhibition, scRNAseq, metabolic glycolysis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-seq identifying regulatory element, unique mouse strain with targeted NRE1 deletion, scRNAseq profiling, multiple orthogonal methods","pmids":["33976173"],"is_preprint":false},{"year":2021,"finding":"NAMPT-derived NAD+ fuels PARP1 hyperactivation, which drives parthanatos cell death and skin inflammation; inhibition of NAMPT, PARP1, or NADPH oxidases reduces oxidative stress, keratinocyte DNA damage, and inflammation in zebrafish skin inflammation models; aberrant NAMPT and PARP activity, together with AIFM1 nuclear translocation, were observed in lesional psoriasis patient skin.","method":"Genetic and pharmacological inhibition (NAMPT, PARP1, NADPH oxidases), PAR glycohydrolase overexpression, zebrafish models, human organotypic 3D skin models, patient tissue analysis","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and pharmacological interventions across animal and human models; NAMPT-NAD+-PARP1-AIFM1 axis established by convergent evidence","pmids":["34748530"],"is_preprint":false},{"year":2021,"finding":"REV-ERB nuclear receptors (REV-ERBα/β) in cardiomyocytes regulate NAMPT expression via repression of the transcription factor E4BP4; E4BP4 directly represses Nampt through distal cis-regulatory elements; REV-ERB-mediated E4BP4 repression is required for circadian Nampt expression and NAD+ salvage synthesis in heart.","method":"Cardiomyocyte-specific Rev-erb double knockout mice, cardiac phenotype analysis, ChIP (E4BP4 binding to Nampt regulatory elements), gene expression analysis","journal":"Nature cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific double KO mouse model, direct transcription factor binding to Nampt regulatory elements by ChIP, phenotypic characterization of pathway","pmids":["35036997"],"is_preprint":false},{"year":2022,"finding":"miR-146a directly targets the 3'-UTR of NAMPT mRNA to reduce NAMPT expression; AMPK activators (metformin, AICAR) suppress miR-146a expression at the transcriptional level by promoting IKK phosphorylation and attenuating NF-κB activity, thereby relieving repression of NAMPT and enabling NAD+/SIRT activation.","method":"Luciferase reporter assay (miR-146a targeting NAMPT 3'-UTR), miR-146a mimic/inhibitor transfection, AMPK activator treatment, IKK/NF-κB pathway analysis, in vitro and in vivo senescence models","journal":"Signal transduction and targeted therapy","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct 3'-UTR targeting confirmed by luciferase assay, convergent pharmacological and genetic approaches, validated in vitro and in vivo","pmids":["35241643"],"is_preprint":false},{"year":2022,"finding":"AMPK directly phosphorylates NAMPT at Ser314 in response to ionizing radiation within 30 minutes, increasing NAMPT enzymatic activity by enhancing NAMPT binding to its substrate PRPP; this phosphorylation restores NAD+ levels and facilitates DNA repair and cell viability.","method":"In vitro kinase assay, site-directed mutagenesis (S314 phosphorylation site), PRPP binding assays, NAD+ measurement, DNA repair assays in irradiated cells","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with mutagenesis of phosphorylation site, substrate binding assay, functional NAD+ rescue; single lab but multiple orthogonal methods","pmids":["36196536"],"is_preprint":false},{"year":2022,"finding":"NAMPT deletion in myeloid cells in colorectal cancer causes HIF-1α destabilization, reducing M2-like TAM polarization and decreasing efferocytosis; this decreased efferocytosis enhances STING signaling and type I IFN-response gene expression, potentiating cytotoxic T cell anti-tumor activity.","method":"Myeloid-specific Nampt conditional knockout mice, scRNA-seq, HIF-1α destabilization assay, efferocytosis assay, STING signaling assessment, T cell activity assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — myeloid-specific KO mice, scRNA-seq profiling, multiple mechanistic readouts in vivo; multi-step pathway from NAMPT to HIF-1α to efferocytosis to STING established","pmids":["38308188"],"is_preprint":false},{"year":2022,"finding":"NAMPT promotes cell survival under oxidative stress via both SIRT1-dependent p53-CD38 pathway and a SIRT1-independent NRF2-PPARα/AMPKα pathway; NAMPT overexpression rescues mitochondrial membrane potential and content under H2O2 treatment via the NRF2-PPARα/AMPKα axis; NRF2 is identified as a downstream target of NAMPT.","method":"NAMPT overexpression, SIRT1 inhibition/knockdown, NRF2 pathway analysis, mitochondrial membrane potential assay, cell viability under oxidative stress","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain-of-function with defined phenotypic readout and pathway analysis; single lab, limited mutagenesis confirmation","pmids":["31816398"],"is_preprint":false},{"year":2022,"finding":"NAMPT deletion in macrophages reduces phagocytic activity due to insufficient NAD+ needed to produce NADPH for the oxidative burst; NMN treatment rescues NADPH levels and restores superoxide generation via NADPH oxidase; NAMPT-deficient mice show impaired dead-cell clearance and prolonged chronic colitis.","method":"Myeloid-specific Nampt conditional knockout (Namptf/f LysMCre+/-), phagocytosis assay, NADPH/NAD+ measurement, NADPH oxidase activity, NMN rescue, DSS colitis model","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific KO with metabolic rescue by NMN, mechanistic link from NAD+ to NADPH to oxidative burst established in vivo and in vitro","pmids":["35063804"],"is_preprint":false},{"year":2022,"finding":"Lamin A/C null (Lmna-/-) MEFs show reduced NAMPT expression and attenuated SIRT1 activity; ATAC-seq reveals reduced chromatin accessibility at the Nampt gene promoter in Lmna-/- cells; this is associated with reduced NAD+ levels and mitochondrial dysfunction.","method":"Lmna-/- MEF and HGPS fibroblast models, ATAC-seq, NAD+ measurement, SIRT1 activity assay, PGC1α chromatin recruitment analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ATAC-seq providing direct evidence of chromatin regulation of NAMPT promoter; functional consequences established; single lab","pmids":["36099415"],"is_preprint":false},{"year":2022,"finding":"CircRNA FEACR directly binds NAMPT protein and enhances its protein stability, increasing NAMPT-dependent SIRT1 expression, which promotes FOXO1 transcriptional activity by reducing FOXO1 acetylation; FOXO1 upregulates FTH1 transcription to inhibit cardiomyocyte ferroptosis.","method":"RNA pull-down (FEACR binding to NAMPT), gain/loss-of-function experiments, western blotting, NAMPT stability assay, SIRT1/FOXO1/FTH1 pathway analysis","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA pulldown confirming direct circRNA-NAMPT interaction, pathway cascade established with multiple readouts; single lab","pmids":["37370086"],"is_preprint":false},{"year":2022,"finding":"NAMPT-containing microvesicles (MVs) shed by radioresistant glioma stem cells transfer NAMPT to radiosensitive cells; the enzymatic activity of NAMPT within recipient cells is necessary to increase intracellular NAD(H) levels and rescue proliferation of irradiated radiosensitive cells.","method":"Proteomic analysis of MVs, NAMPT-high MV transfer experiments, NAMPT enzymatic activity requirement assays, NAD(H) measurement in recipient cells, radioresistance phenotype assays","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MV transfer established functionally with NAMPT enzymatic activity requirement confirmed; multiple patient-derived GSC lines; single lab","pmids":["37037593"],"is_preprint":false},{"year":2023,"finding":"Low-dose nicotine restores age-related decline in NAMPT activity via SIRT1 binding to NAMPT followed by deacetylation of NAMPT, independent of nicotinic acetylcholine receptors; deacetylation of NAMPT by SIRT1 increases its enzymatic activity and NAD+ synthesis.","method":"Co-immunoprecipitation (SIRT1-NAMPT binding), NAMPT enzymatic activity assay, nicotinic receptor blockade, in vivo aging mouse model, 18F-FDG PET imaging","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for binding, enzymatic activity assay for functional consequence, receptor blockade to rule out canonical signaling; single lab","pmids":["36797299"],"is_preprint":false},{"year":2023,"finding":"NAMPT-dependent NAD+ control of the molecular clock varies substantially between tissues: brown adipose tissue (BAT) requires NAMPT for clock amplitude; skeletal muscle clock is refractory to NAMPT loss; NAMPT differentially orchestrates oscillation of clock-controlled gene networks and metabolites, including TCA cycle intermediates, in a tissue-specific manner.","method":"Tissue-specific Nampt knockout mouse models, transcriptomic analysis, metabolomics (TCA cycle intermediates), circadian amplitude measurements, cold challenge assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO models, transcriptomics and metabolomics across multiple tissues, functional circadian and metabolic phenotyping","pmids":["36996103"],"is_preprint":false},{"year":2024,"finding":"NAMPT inhibition in macrophages causes HIF-1α destabilization, directly linking NAMPT-dependent NAD+ production to HIF-1α stability and M2-like macrophage polarization.","method":"Myeloid-specific Nampt KO, HIF-1α protein stability assay, macrophage polarization markers","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — specific KO with defined molecular readout; HIF-1α destabilization identified but mechanism linking NAD+ to HIF-1α stability not fully resolved; single lab","pmids":["38308188"],"is_preprint":false},{"year":2023,"finding":"Small molecule NAMPT positive allosteric modulators (N-PAMs) bind to the 'rear channel' of NAMPT, increasing enzyme activity and alleviating feedback inhibition by NAM and NAD+; binding affinity to the rear channel correlates directly with potency for enzyme activation, and activation translates to elevated cellular NAD+.","method":"Structure-activity relationship study (>70 compounds), rear channel binding affinity assays, enzymatic activity assays, cellular NAD+ measurement","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic reconstitution with binding site characterization; structure-activity correlation establishes allosteric mechanism; single lab","pmids":["38096366"],"is_preprint":false},{"year":2024,"finding":"NAMPT inhibition in macrophages reduces their efferocytosis activity due to insufficient NAD+-derived NADPH for oxidative burst; decreased efferocytosis activates STING signaling promoting type I IFN response genes.","method":"Myeloid-specific Nampt KO, efferocytosis assay, NADPH measurement, STING pathway assays, IFN-response gene expression","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific KO linking NAMPT/NAD+/NADPH to efferocytosis and downstream STING activation; multiple orthogonal readouts; single lab","pmids":["38308188"],"is_preprint":false},{"year":2012,"finding":"PBEF (NAMPT) induces VEGF secretion by amniotic epithelial cells and increases VEGFR2 expression in placental amniotic epithelial cells (but not reflected AEC); PBEF combined with VEGF increases permeability of the placental amnion, measured by DCF transfer across amnion explants.","method":"Primary human amniotic epithelial cell (AEC) cultures, VEGF ELISA, VEGFR2 expression analysis, amnion permeability assay with DCF tracer","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct functional assay of amnion permeability with pharmacological treatment; receptor upregulation by PBEF established; single lab","pmids":["23151382"],"is_preprint":false},{"year":2015,"finding":"NAMPT inhibits progesterone secretion in hen granulosa cells via its enzymatic (NAMPT) activity; recombinant NAMPT (100 ng/ml) reduces basal and IGF1-induced progesterone secretion and decreases STAR and HSD3B protein levels and MAPK3/1 phosphorylation; the effect is abolished by FK866, confirming enzymatic activity dependence.","method":"Primary hen granulosa cell cultures, FK866 enzymatic inhibition, progesterone ELISA, western blotting for STAR/HSD3B, MAPK3/1 phosphorylation assay","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FK866 enzymatic inhibition confirms mechanism dependency; multiple signaling readouts; single lab with avian model","pmids":["25918435"],"is_preprint":false},{"year":2020,"finding":"NAMPT inhibition in hypothalamic neurons by ICV-administered FK866 completely ablates fasting- and ghrelin-induced increases in food intake without causing malaise; NAMPT inhibition in primary hypothalamic neurons reduces NAD+, increases reactive oxygen species, affects mitochondrial respiration, and alters expression of Agrp and Pomc.","method":"ICV FK866 administration, metabolic cage food intake measurement, primary hypothalamic neuron FK866 treatment, ROS measurement, mitochondrial respiration assay, Agrp/Pomc gene expression","journal":"Acta physiologica (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with defined behavioral and molecular readouts in vivo and in vitro; single lab","pmids":["31900990"],"is_preprint":false},{"year":2022,"finding":"NAMPT promotes IFNγ production by CD4+ T cells in lupus nephritis by supporting aerobic glycolysis and mitochondrial respiration through NAD+ production; NAMPT promotes translational efficiency of Ifng mRNA in CD4+ T cells; FK866 or siRNA knockdown suppresses IFNγ production and reduces kidney damage in lupus mice.","method":"NAMPT inhibition by FK866 and siRNA in CD4+ T cells from LN patients and MRL/lpr mice, glycolysis/mitochondrial respiration assay, translational efficiency assay, in vivo siRNA delivery with kidney damage scoring","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — convergent pharmacological and genetic inhibition with defined metabolic and translational readouts; in vivo and patient cell validation; single lab","pmids":["36146932"],"is_preprint":false},{"year":2024,"finding":"NAMPT inhibition by FK866 enhances acetylation of LDHA in cells, reducing LDHA activity and decreasing lactate production; NAMPT functions upstream of SIRT2 to regulate LDHA acetylation status, forming a Nampt/SIRT2/LDHA pathway that controls lactate production in granulosa cells.","method":"Co-immunoprecipitation (LDHA acetylation state), FK866 NAMPT inhibition, SIRT2 inhibition, NAMPT inhibitor and NMN supplementation in PCOS rat model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for acetylation state, pharmacological pathway dissection; in vivo and in vitro convergent evidence; single lab","pmids":["39489197"],"is_preprint":false},{"year":2022,"finding":"NAMPT depletion in hippocampal CA1 neurons causes mitochondrial swelling and decreased mitochondrial number, cognitive deficiency, and increased intracellular Aβ aggregation; in primary neurons, FK866 inhibition of NAMPT drops mitochondrial membrane potential and decreases neurite branching in a dose-dependent manner.","method":"Hippocampus-specific Nampt KO (rAAV-hSyn-Cre), transmission electron microscopy, immunofluorescence, FK866 inhibition in primary neurons, mitochondrial membrane potential assay","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — neuron-specific KO with ultrastructural and functional phenotyping; pharmacological confirmation in primary cells; single lab","pmids":["36441480"],"is_preprint":false}],"current_model":"NAMPT is a dimeric type II phosphoribosyltransferase that catalyzes the rate-limiting conversion of nicotinamide to nicotinamide mononucleotide (NMN) using phosphoribosyl pyrophosphate (PRPP) and ATP—a reaction allosterically regulated by a rear-channel binding site and post-translationally controlled by AMPK-mediated Ser314 phosphorylation and SIRT1-mediated deacetylation; by sustaining cellular and systemic NAD+ pools, intracellular NAMPT governs the activity of NAD+-dependent enzymes (SIRT1, PARP1, CD38) to control insulin secretion in beta cells, IFNγ production in T cells, glycolysis-linked macrophage effector functions (phagocytosis, M1/M2 polarization via HIF-1α), neuronal mitochondrial integrity, and circadian metabolic oscillations in a tissue-specific manner; extracellular NAMPT functions as a cytokine by directly ligating TLR4 (via a structurally distinct loop region S402–N412) to activate NF-κB signaling, and can also signal through Ccr5 on muscle stem cells to promote their proliferation, while its pro-inflammatory enzymatic activity drives MAPK–NF-κB cascades and PARP1-mediated parthanatos; NAMPT expression is transcriptionally regulated by STAT1 (via a conserved intronic element NRE1 induced by IFN-γ), by the circadian REV-ERB/E4BP4 axis, and post-transcriptionally by miR-146a targeting its 3'-UTR."},"narrative":{"mechanistic_narrative":"NAMPT is the rate-limiting enzyme of the mammalian NAD+ salvage pathway, a dimeric type II phosphoribosyltransferase that converts nicotinamide to nicotinamide mononucleotide (NMN) using PRPP, sustaining cellular and systemic NAD+ pools that govern diverse metabolic and inflammatory programs [PMID:16783373, PMID:17268245, PMID:17983582]. By providing the NAD+ that drives NAD+-dependent enzymes, intracellular NAMPT controls glucose-stimulated insulin secretion in pancreatic islets [PMID:17983582], supports SIRT1- and PARP1-dependent signaling [PMID:23435312], fuels macrophage glycolysis, HIF-1α stabilization, and the NADPH-dependent oxidative burst needed for phagocytosis and efferocytosis [PMID:35063804, PMID:38308188], promotes CD4+ T cell IFNγ production through aerobic glycolysis and Ifng translation [PMID:36146932], and maintains neuronal mitochondrial integrity [PMID:36441480]. The enzyme's activity is regulated allosterically through a rear-channel binding site that relieves NAM/NAD+ feedback inhibition [PMID:38096366] and post-translationally by AMPK-mediated Ser314 phosphorylation, which enhances PRPP binding to restore NAD+ for DNA repair [PMID:36196536], and by SIRT1-mediated deacetylation that boosts catalytic activity [PMID:36797299]. NAMPT also functions extracellularly: hepatocytes and glucose-stimulated islets secrete an enzymatically active dimeric form [PMID:19912992, PMID:23536823], which acts as a pro-inflammatory mediator that requires its enzymatic activity to drive MAPK–NF-κB cascades in macrophages and synovial fibroblasts [PMID:21327328, PMID:22767598], directly ligates TLR4 via a protruding S402–N412 loop to activate NF-κB [PMID:26272519], signals through Ccr5 on muscle stem cells to drive proliferation [PMID:33568815], and fuels PARP1 hyperactivation and parthanatos in skin inflammation [PMID:34748530]. NAMPT expression is transcriptionally controlled by STAT1 acting at the intronic NRE1 enhancer in response to IFN-γ [PMID:33976173] and by the circadian REV-ERB/E4BP4 axis [PMID:35036997], with NAMPT-dependent NAD+ in turn driving tissue-specific circadian metabolic oscillations [PMID:36996103]; expression is also tuned post-transcriptionally by miR-146a targeting its 3'-UTR [PMID:35241643].","teleology":[{"year":2006,"claim":"Establishing the enzyme class and catalytic architecture was the foundational question; the crystal structure defined NAMPT as a dimeric type II phosphoribosyltransferase and revealed how it synthesizes NMN from nicotinamide.","evidence":"X-ray crystallography with and without NMN product","pmids":["16783373"],"confidence":"High","gaps":["Did not establish in vivo regulation of the enzyme","Allosteric and post-translational control sites not resolved"]},{"year":2007,"claim":"Whether NAMPT was rate-limiting for NAD+ biosynthesis and physiologically essential was unresolved; haplodeficiency and chemical inhibition causing NAD+ and insulin-secretion defects rescuable by NMN established its role as the rate-limiting salvage enzyme.","evidence":"Genetic haplodeficiency mouse, chemical inhibition, glucose-stimulated insulin secretion, NMN rescue, enzymatic assays","pmids":["17983582","17268245","16783373"],"confidence":"High","gaps":["Tissue-specific contributions not dissected","Did not address extracellular function"]},{"year":2009,"claim":"Whether secreted NAMPT retained catalytic function was open; hepatocyte-secreted NAMPT was shown to be dimeric and enzymatically active, establishing an extracellular pool comparable to the intracellular form.","evidence":"Size exclusion chromatography and enzymatic assays on HepG2 and primary hepatocyte secretions","pmids":["19912992"],"confidence":"Medium","gaps":["Secretion mechanism not defined","Physiological function of extracellular pool not addressed"]},{"year":2008,"claim":"Early functional studies asked whether NAMPT/PBEF acts in inflammation; reciprocal gain/loss-of-function linked it to IL-8 secretion, IL-1β-mediated permeability, and mitochondrial/oxidative-stress interactions in pulmonary cells.","evidence":"Overexpression and siRNA knockdown in A549/HPAEC, cytokine and permeability assays, Co-IP with ND1/ferritin/IFITM3","pmids":["18996492","18486613"],"confidence":"Medium","gaps":["Interaction mechanism with mitochondrial partners unresolved","Enzymatic vs cytokine activity not separated"]},{"year":2013,"claim":"Whether the pro-inflammatory and pro-tumor actions of NAMPT require its catalytic activity was tested; pharmacological/genetic inhibition with NAD+/NMN rescue confirmed enzymatic dependence in myeloma growth, MAPK–NF-κB inflammation, and glucose-dependent islet secretion.","evidence":"APO866/FK866 inhibition, siRNA, NAD+/NMN rescue, PARP-1/SIRT-1 assays, xenografts, pathway inhibitors, secretion assays","pmids":["23435312","21327328","22767598","23536823"],"confidence":"High","gaps":["Receptor mediating extracellular signaling not yet identified","Distinction between NMN production and direct ligand activity incomplete"]},{"year":2015,"claim":"The receptor for extracellular NAMPT cytokine activity was unknown; computational and functional analysis identified direct TLR4 ligation via an LPS-like S402–N412 loop driving NF-κB and lung injury.","evidence":"Computational structural analysis, TLR4/NF-κB reporter assays, VILI mouse model","pmids":["26272519"],"confidence":"Medium","gaps":["Direct binding partly inferred computationally","Relationship between TLR4 ligation and enzymatic activity unresolved"]},{"year":2021,"claim":"How NAMPT couples to specific cellular outcomes was addressed across systems; macrophage-secreted NAMPT was found to signal through Ccr5 on muscle stem cells, IFN-γ/STAT1 to drive Nampt via the NRE1 enhancer for M1 macrophage glycolysis and anti-tumor immunity, REV-ERB/E4BP4 to set circadian Nampt expression, and NAMPT-derived NAD+ to fuel PARP1-driven parthanatos in skin.","evidence":"Zebrafish injury/live imaging, scRNAseq, ChIP-seq, NRE1 and Rev-erb KO mice, PARP1/NADPH-oxidase inhibition, human skin models","pmids":["33568815","33976173","35036997","34748530"],"confidence":"High","gaps":["Ccr5 ligation mechanism distinct from enzymatic NAD+ not fully defined","How NAD+ flux selectively tunes specific effector genes incomplete"]},{"year":2022,"claim":"The post-transcriptional and post-translational control of NAMPT, and its downstream NAD+-dependent effector axes, were dissected; AMPK Ser314 phosphorylation enhances PRPP binding and DNA repair, miR-146a represses NAMPT via its 3'-UTR, lamin A/C and circRNA FEACR modulate NAMPT expression/stability, and myeloid NAMPT controls HIF-1α, efferocytosis, STING, and oxidative burst.","evidence":"In vitro kinase assay/S314 mutagenesis, luciferase 3'-UTR assay, ATAC-seq, RNA pull-down, myeloid-specific KO mice, scRNA-seq, NMN rescue, mitochondrial/SIRT1 assays","pmids":["36196536","35241643","36099415","37370086","38308188","35063804","31816398"],"confidence":"High","gaps":["Mechanism linking NAD+ to HIF-1α stability not fully resolved","Integration of multiple regulatory inputs in vivo unclear"]},{"year":2023,"claim":"Allosteric activation and SIRT1 feedback regulation were defined; rear-channel positive allosteric modulators relieve NAM/NAD+ feedback inhibition, and SIRT1 binds and deacetylates NAMPT to raise its activity, while tissue-specific NAD+ control of the clock was mapped.","evidence":"SAR study with rear-channel binding assays, Co-IP, enzymatic assays, tissue-specific KO mice, transcriptomics/metabolomics","pmids":["38096366","36797299","36996103"],"confidence":"Medium","gaps":["Structural basis of SIRT1-NAMPT interaction not solved","Why some tissues are refractory to NAMPT loss unexplained"]},{"year":2024,"claim":"NAMPT-controlled deacetylation of metabolic enzymes was added to the model, with the Nampt/SIRT2/LDHA axis shown to regulate lactate production.","evidence":"Co-IP for LDHA acetylation, FK866/SIRT2 inhibition, NMN supplementation, PCOS rat model","pmids":["39489197"],"confidence":"Medium","gaps":["Direct vs NAD+-dependent regulation of SIRT2 not separated","Generality across cell types untested"]},{"year":null,"claim":"How the enzymatic (NAD+-generating) and non-enzymatic cytokine/receptor-ligand functions of extracellular NAMPT are mechanistically partitioned, and how a single secreted protein engages distinct receptors (TLR4, Ccr5) in different tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of NAMPT bound to TLR4 or Ccr5","Secretion/export route of intracellular NAMPT undefined","Relative contribution of enzymatic vs ligand activity in vivo not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,28]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[10,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[28]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,21]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,8,10,13]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[24]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,14,21,33]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,10,11]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[16,26]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[15]}],"complexes":[],"partners":["TLR4","CCR5","SIRT1","PARP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43490","full_name":"Nicotinamide phosphoribosyltransferase","aliases":["Pre-B-cell colony-enhancing factor 1","Pre-B cell-enhancing factor","Visfatin"],"length_aa":491,"mass_kda":55.5,"function":"Catalyzes the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD. It is the rate limiting component in the mammalian NAD biosynthesis pathway. The secreted form behaves both as a cytokine with immunomodulating properties and an adipokine with anti-diabetic properties, it has no enzymatic activity, partly because of lack of activation by ATP, which has a low level in extracellular space and plasma. Plays a role in the modulation of circadian clock function. NAMPT-dependent oscillatory production of NAD regulates oscillation of clock target gene expression by releasing the core clock component: CLOCK-BMAL1 heterodimer from NAD-dependent SIRT1-mediated suppression (By similarity)","subcellular_location":"Nucleus; Cytoplasm; Secreted","url":"https://www.uniprot.org/uniprotkb/P43490/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NAMPT","classification":"Not Classified","n_dependent_lines":428,"n_total_lines":1208,"dependency_fraction":0.3543046357615894},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NAMPT","total_profiled":1310},"omim":[{"mim_id":"611552","title":"NICOTINATE PHOSPHORIBOSYLTRANSFERASE; NAPRT","url":"https://www.omim.org/entry/611552"},{"mim_id":"608764","title":"NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE; NAMPT","url":"https://www.omim.org/entry/608764"},{"mim_id":"604517","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR 1, ALPHA; PPARGC1A","url":"https://www.omim.org/entry/604517"},{"mim_id":"604479","title":"SIRTUIN 1; SIRT1","url":"https://www.omim.org/entry/604479"},{"mim_id":"601851","title":"CLOCK CIRCADIAN REGULATOR; CLOCK","url":"https://www.omim.org/entry/601851"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear speckles","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":339.4}],"url":"https://www.proteinatlas.org/search/NAMPT"},"hgnc":{"alias_symbol":["PBEF"],"prev_symbol":["PBEF1"]},"alphafold":{"accession":"P43490","domains":[{"cath_id":"3.20.140.10","chopping":"10-159_398-480","consensus_level":"high","plddt":94.1142,"start":10,"end":480},{"cath_id":"3.20.20.70","chopping":"175-381","consensus_level":"medium","plddt":97.1008,"start":175,"end":381}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43490","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43490-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43490-F1-predicted_aligned_error_v6.png","plddt_mean":94.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NAMPT","jax_strain_url":"https://www.jax.org/strain/search?query=NAMPT"},"sequence":{"accession":"P43490","fasta_url":"https://rest.uniprot.org/uniprotkb/P43490.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43490/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43490"}},"corpus_meta":[{"pmid":"17983582","id":"PMC_17983582","title":"Nampt/PBEF/Visfatin regulates insulin secretion in beta cells as a systemic NAD biosynthetic enzyme.","date":"2007","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17983582","citation_count":766,"is_preprint":false},{"pmid":"26215259","id":"PMC_26215259","title":"Physiological and pathophysiological roles of NAMPT and NAD metabolism.","date":"2015","source":"Nature reviews. 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colony-enhancing factor (PBEF)/visfatin: a novel mediator of innate immunity.","date":"2008","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/18252866","citation_count":232,"is_preprint":false},{"pmid":"25709099","id":"PMC_25709099","title":"Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) as a therapeutic strategy in cancer.","date":"2015","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/25709099","citation_count":212,"is_preprint":false},{"pmid":"19149599","id":"PMC_19149599","title":"Nicotinamide phosphoribosyltransferase (Nampt): a link between NAD biology, metabolism, and diseases.","date":"2009","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/19149599","citation_count":198,"is_preprint":false},{"pmid":"24003918","id":"PMC_24003918","title":"The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing.","date":"2013","source":"Diabetes, obesity & 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1979)","url":"https://pubmed.ncbi.nlm.nih.gov/19016657","citation_count":115,"is_preprint":false},{"pmid":"37370086","id":"PMC_37370086","title":"Circular RNA FEACR inhibits ferroptosis and alleviates myocardial ischemia/reperfusion injury by interacting with NAMPT.","date":"2023","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/37370086","citation_count":101,"is_preprint":false},{"pmid":"16842957","id":"PMC_16842957","title":"Nampt/PBEF/Visfatin: a regulator of mammalian health and longevity?","date":"2006","source":"Experimental gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/16842957","citation_count":89,"is_preprint":false},{"pmid":"24479481","id":"PMC_24479481","title":"Expression and function of visfatin (Nampt), an adipokine-enzyme involved in inflammatory pathways of osteoarthritis.","date":"2014","source":"Arthritis research & 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of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/25603815","citation_count":43,"is_preprint":false},{"pmid":"29886033","id":"PMC_29886033","title":"Down-regulation of NAMPT expression by mir-206 reduces cell survival of breast cancer cells.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29886033","citation_count":42,"is_preprint":false},{"pmid":"23536823","id":"PMC_23536823","title":"Expression and regulation of nampt in human islets.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23536823","citation_count":40,"is_preprint":false},{"pmid":"35152912","id":"PMC_35152912","title":"circPTPN4 regulates myogenesis via the miR-499-3p/NAMPT axis.","date":"2022","source":"Journal of animal science and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/35152912","citation_count":37,"is_preprint":false},{"pmid":"36442664","id":"PMC_36442664","title":"Making Protein Degradation Visible: Discovery of Theranostic PROTACs for Detecting and Degrading NAMPT.","date":"2022","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36442664","citation_count":35,"is_preprint":false},{"pmid":"31710121","id":"PMC_31710121","title":"NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31710121","citation_count":34,"is_preprint":false},{"pmid":"25918435","id":"PMC_25918435","title":"Expression and effect of NAMPT (visfatin) on progesterone secretion in hen granulosa cells.","date":"2015","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25918435","citation_count":34,"is_preprint":false},{"pmid":"21484571","id":"PMC_21484571","title":"Nampt and its potential role in inflammation and type 2 diabetes.","date":"2011","source":"Handbook of experimental 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26485210","citation_count":28,"is_preprint":false},{"pmid":"38282119","id":"PMC_38282119","title":"Photoswitchable PROTACs for Reversible and Spatiotemporal Regulation of NAMPT and NAD.","date":"2024","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/38282119","citation_count":28,"is_preprint":false},{"pmid":"36323324","id":"PMC_36323324","title":"Addressing the Enzyme-independent tumor-promoting function of NAMPT via PROTAC-mediated degradation.","date":"2022","source":"Cell chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/36323324","citation_count":28,"is_preprint":false},{"pmid":"31816398","id":"PMC_31816398","title":"NAMPT maintains mitochondria content via NRF2-PPARα/AMPKα pathway to promote cell survival under oxidative stress.","date":"2019","source":"Cellular 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Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19074645","citation_count":27,"is_preprint":false},{"pmid":"31338216","id":"PMC_31338216","title":"Targeting NAMPT as a therapeutic strategy against stroke.","date":"2019","source":"Stroke and vascular neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31338216","citation_count":26,"is_preprint":false},{"pmid":"23151382","id":"PMC_23151382","title":"Pre-B cell colony enhancing factor (PBEF/NAMPT/Visfatin) and vascular endothelial growth factor (VEGF) cooperate to increase the permeability of the human placental amnion.","date":"2012","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/23151382","citation_count":26,"is_preprint":false},{"pmid":"31900990","id":"PMC_31900990","title":"Fasting- and ghrelin-induced food intake is regulated by NAMPT in the hypothalamus.","date":"2020","source":"Acta physiologica (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31900990","citation_count":26,"is_preprint":false},{"pmid":"30794635","id":"PMC_30794635","title":"NAMPT overexpression alleviates alcohol-induced hepatic steatosis in mice.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30794635","citation_count":26,"is_preprint":false},{"pmid":"33038343","id":"PMC_33038343","title":"Non-canonical roles of NAMPT and PARP in inflammation.","date":"2020","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33038343","citation_count":25,"is_preprint":false},{"pmid":"28468779","id":"PMC_28468779","title":"Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors.","date":"2017","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28468779","citation_count":25,"is_preprint":false},{"pmid":"37413882","id":"PMC_37413882","title":"Recent advances of targeting nicotinamide phosphoribosyltransferase (NAMPT) for cancer drug discovery.","date":"2023","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37413882","citation_count":25,"is_preprint":false},{"pmid":"21833174","id":"PMC_21833174","title":"Visfatin/PBEF/Nampt: A New Cardiovascular Target?","date":"2010","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21833174","citation_count":24,"is_preprint":false},{"pmid":"38092728","id":"PMC_38092728","title":"Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38092728","citation_count":23,"is_preprint":false},{"pmid":"17512309","id":"PMC_17512309","title":"Effects of genetic variation in the visfatin gene (PBEF1) on obesity, glucose metabolism, and blood pressure in children.","date":"2007","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/17512309","citation_count":22,"is_preprint":false},{"pmid":"20358348","id":"PMC_20358348","title":"Lack of direct insulin-like action of visfatin/Nampt/PBEF1 in human adipocytes.","date":"2009","source":"Journal of physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20358348","citation_count":22,"is_preprint":false},{"pmid":"18486613","id":"PMC_18486613","title":"Interactions between PBEF and oxidative stress proteins--a potential new mechanism underlying PBEF in the pathogenesis of acute lung injury.","date":"2008","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/18486613","citation_count":22,"is_preprint":false},{"pmid":"39489197","id":"PMC_39489197","title":"Nampt/SIRT2/LDHA pathway-mediated lactate production regulates follicular dysplasia in polycystic ovary syndrome.","date":"2024","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39489197","citation_count":21,"is_preprint":false},{"pmid":"17983577","id":"PMC_17983577","title":"Nampt/PBEF/Visfatin: a new player in beta cell physiology and in metabolic diseases?","date":"2007","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17983577","citation_count":21,"is_preprint":false},{"pmid":"38244254","id":"PMC_38244254","title":"Drug discovery targeting nicotinamide phosphoribosyltransferase (NAMPT): Updated progress and perspectives.","date":"2024","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38244254","citation_count":21,"is_preprint":false},{"pmid":"39513038","id":"PMC_39513038","title":"The function of nicotinamide phosphoribosyl transferase (NAMPT) and its role in diseases.","date":"2024","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/39513038","citation_count":20,"is_preprint":false},{"pmid":"35565188","id":"PMC_35565188","title":"Updated Functional Roles of NAMPT in Carcinogenesis and Therapeutic Niches.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/35565188","citation_count":20,"is_preprint":false},{"pmid":"36077374","id":"PMC_36077374","title":"NAD/NAMPT and mTOR Pathways in Melanoma: Drivers of Drug Resistance and Prospective Therapeutic Targets.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36077374","citation_count":19,"is_preprint":false},{"pmid":"38173843","id":"PMC_38173843","title":"Transcriptome analysis reveals therapeutic potential of NAMPT in protecting against abdominal aortic aneurysm in human and mouse.","date":"2023","source":"Bioactive materials","url":"https://pubmed.ncbi.nlm.nih.gov/38173843","citation_count":19,"is_preprint":false},{"pmid":"36196536","id":"PMC_36196536","title":"AMPK phosphorylates NAMPT to regulate NAD+ homeostasis under ionizing radiation.","date":"2022","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/36196536","citation_count":19,"is_preprint":false},{"pmid":"22430142","id":"PMC_22430142","title":"NAMPT pathway is involved in the FOXO3a-mediated regulation of GADD45A expression.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/22430142","citation_count":19,"is_preprint":false},{"pmid":"18940394","id":"PMC_18940394","title":"The visfatin (PBEF1) G-948T gene polymorphism is associated with increased high-density lipoprotein cholesterol in obese subjects.","date":"2008","source":"Metabolism: clinical and 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chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33522796","citation_count":17,"is_preprint":false},{"pmid":"24287278","id":"PMC_24287278","title":"Endogenous NAMPT dampens chemokine expression and apoptotic responses in stressed tubular cells.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24287278","citation_count":17,"is_preprint":false},{"pmid":"36899911","id":"PMC_36899911","title":"The NAMPT Inhibitor FK866 in Combination with Cisplatin Reduces Cholangiocarcinoma Cells Growth.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36899911","citation_count":16,"is_preprint":false},{"pmid":"37037593","id":"PMC_37037593","title":"Proteomic analysis reveals microvesicles containing NAMPT as mediators of radioresistance in glioma.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/37037593","citation_count":16,"is_preprint":false},{"pmid":"35903330","id":"PMC_35903330","title":"From Rate-Limiting Enzyme to Therapeutic Target: The Promise of NAMPT in Neurodegenerative Diseases.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35903330","citation_count":15,"is_preprint":false},{"pmid":"38096366","id":"PMC_38096366","title":"Synthesis, Optimization, and Structure-Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs).","date":"2023","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38096366","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47236,"output_tokens":9089,"usd":0.139021,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19580,"output_tokens":4443,"usd":0.104487,"stage2_stop_reason":"end_turn"},"total_usd":0.243508,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of Nampt reveals it is a dimeric type II phosphoribosyltransferase; the structure in the presence and absence of NMN provides insights into the enzymatic mechanism of NMN synthesis from nicotinamide.\",\n      \"method\": \"X-ray crystallography (crystal structure determination with and without NMN product)\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with and without substrate/product, directly establishing enzyme class and catalytic mechanism\",\n      \"pmids\": [\"16783373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Intracellular NAMPT (iNampt) is an essential NAD biosynthetic enzyme; haplodeficiency or chemical inhibition causes defects in NAD biosynthesis and glucose-stimulated insulin secretion in pancreatic islets, correctable by NMN supplementation. Extracellular NAMPT (eNampt) does not exert insulin-mimetic effects but exhibits robust NAD biosynthetic activity.\",\n      \"method\": \"Genetic haplodeficiency mouse model, chemical inhibition, in vitro and in vivo glucose-stimulated insulin secretion assays, NMN rescue experiments, plasma NMN measurement\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, pharmacological inhibition, rescue with enzymatic product) in vivo and in vitro, replicated across conditions\",\n      \"pmids\": [\"17983582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NAMPT is the rate-limiting enzyme that converts nicotinamide to nicotinamide mononucleotide (NMN) in the mammalian NAD biosynthetic salvage pathway from nicotinamide.\",\n      \"method\": \"Enzymatic activity assay, genetic and pharmacological perturbation of NAD biosynthesis\",\n      \"journal\": \"Current opinion in gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — established by direct enzymatic assays across multiple independent studies\",\n      \"pmids\": [\"17268245\", \"17983582\", \"16783373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Human hepatocytes constitutively release NAMPT into the extracellular space in a time-dependent manner; secreted NAMPT is primarily dimeric and exhibits in vitro NAD biosynthetic enzymatic activity comparable to intracellular NAMPT.\",\n      \"method\": \"Size exclusion chromatography, enzymatic activity assay, cell culture secretion experiments with HepG2 and primary human hepatocytes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity confirmed on secreted protein with two cell models; single lab\",\n      \"pmids\": [\"19912992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NAMPT (PBEF) interacts with NADH dehydrogenase subunit 1 (ND1), ferritin light chain, and IFITM3 in human pulmonary vascular endothelial cells; PBEF overexpression increases these interactions and intracellular oxidative stress, attenuatable by rotenone.\",\n      \"method\": \"Protein interaction identification and validation (co-immunoprecipitation/pulldown), overexpression, rotenone inhibition, computational interaction modeling\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, validated by pulldown and modeling, but mechanism of interaction not fully resolved\",\n      \"pmids\": [\"18486613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NAMPT (PBEF) overexpression augments IL-8 secretion and IL-1β-mediated cell permeability in pulmonary vascular endothelial and epithelial cells; knockdown of PBEF inhibits IL-1β-stimulated IL-8 secretion and reduces cell permeability, establishing PBEF as a regulator of pulmonary inflammation and permeability.\",\n      \"method\": \"PBEF overexpression and siRNA knockdown in A549 and HPAEC cells, cytokine secretion assay, permeability assay\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined cellular phenotype readouts; single lab\",\n      \"pmids\": [\"18996492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Extracellular NAMPT (visfatin) induces EMMPRIN and MMP-9 expression in macrophages via NAMPT enzymatic activity (NMN production) activating the MAPK (p38, ERK1/2)–NF-κB signaling pathway; this pro-inflammatory action is not prevented by insulin receptor blockade.\",\n      \"method\": \"Pharmacological inhibition (FK866, p38 inhibitor, ERK1/2 inhibitor, NF-κB inhibitor), exogenous NMN supplementation, RT-PCR, western blotting, gelatin zymography, THP-1 macrophage cell line\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors used orthogonally; NMN mimicry confirms enzymatic mechanism; single lab\",\n      \"pmids\": [\"21327328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"NAMPT (PBEF1) enzymatic activity is required for myeloma cell growth and osteoclast activity; inhibition by APO866 depletes NAD+, reduces PARP-1 and SIRT-1 activity, and induces apoptosis; effects are rescued by extracellular NAD+ or nicotinamide supplementation. PBEF1 knockdown phenocopies APO866 inhibition.\",\n      \"method\": \"APO866 pharmacological inhibition, PBEF1 siRNA knockdown, NAD+ rescue, PARP-1/SIRT-1 activity assays, SCID-rab in vivo xenograft model\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological and genetic inhibition with NAD+ rescue confirming on-target mechanism; in vivo validation\",\n      \"pmids\": [\"23435312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Human islets secrete enzymatically active eNAMPT in a glucose-dependent manner requiring membrane depolarization; glucose (20 mM) increases both eNAMPT secretion and NAMPT mRNA levels; secretion is attenuated by diazoxide and nifedipine (membrane depolarization inhibitors).\",\n      \"method\": \"Static glucose-stimulated insulin secretion assay, ELISA, enzymatic activity assay on secreted NAMPT, pharmacological inhibitors (diazoxide, nifedipine), qRT-PCR, immunofluorescence/confocal imaging\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity confirmed on secreted protein; secretion mechanism dissected with specific inhibitors; single lab\",\n      \"pmids\": [\"23536823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Visfatin/Nampt is present in human OA joint tissues in a homodimeric, enzymatically active conformation; inhibition of Nampt enzymatic activity by APO866 reduces pro-inflammatory cytokine (IL-6, KC, MCP-1) mRNA and protein expression in chondrocytes and osteoblasts, demonstrating that the pro-inflammatory action of visfatin requires its enzymatic (NAMPT) activity.\",\n      \"method\": \"Western blot, ELISA, size exclusion chromatography, colorimetric enzymatic activity assay, APO866 pharmacological inhibition, RT-PCR, primary murine chondrocyte and osteoblast cultures\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity confirmed ex vivo and in vitro; APO866 inhibition links enzymatic activity to pro-inflammatory effects; single lab\",\n      \"pmids\": [\"24479481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Extracellular NAMPT/PBEF directly ligates Toll-like receptor 4 (TLR4) to induce NF-κB transcriptional activity and inflammatory lung injury; computational analysis shows NAMPT shares ~30% sequence identity and structural similarity with TLR4-binding protein MD-2; unlike MD-2, NAMPT alone produces robust TLR4 activation, likely via a protruding region (S402-N412) with structural similarity to LPS.\",\n      \"method\": \"Computational structural analysis, TLR4 signaling reporter assays, NF-κB transcriptional activity assays, VILI mouse model with reduced NAMPT bioavailability\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct TLR4 ligation supported by computational structural evidence and functional signaling assays; single lab, mechanism partially inferred computationally\",\n      \"pmids\": [\"26272519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Visfatin/PBEF induces high amounts of chemokines (IL-8, MCP-1), IL-6, and MMP-3 in rheumatoid arthritis synovial fibroblasts (RASFs) through p38 MAPK phosphorylation; p38 MAPK inhibition strongly reduces these effects; visfatin/PBEF also increases directed and general fibroblast motility.\",\n      \"method\": \"Affymetrix array, RT-PCR, immunoassay, p38 MAPK inhibitor, primary RASF cultures, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibitor confirms p38 MAPK involvement; multiple readouts; single lab\",\n      \"pmids\": [\"22767598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NAMPT pathway controls GADD45A expression via FOXO3a acetylation: NAMPT overexpression decreases GADD45A expression while FK866 inhibition of NAMPT increases it; increased GADD45A expression under NAMPT inhibition involves FOXO3a acetylation (mediated through reduced SIRT1 activity).\",\n      \"method\": \"NAMPT overexpression, FK866 inhibition, SIRT1 shRNA knockdown, gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent pharmacological and genetic approaches linking NAMPT/NAD+/SIRT1 to FOXO3a acetylation and GADD45A; single lab\",\n      \"pmids\": [\"22430142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Macrophage-derived NAMPT is required for muscle satellite cell (stem cell) proliferation after injury; specific 'dwelling' macrophages secrete NAMPT, which acts through the C-C motif chemokine receptor type 5 (Ccr5) expressed on muscle stem cells to stimulate proliferation.\",\n      \"method\": \"Zebrafish muscle injury models, live imaging of cell interactions, single-cell transcriptomics, genetic/pharmacological perturbation of NAMPT secretion\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo live imaging, genetic perturbations, single-cell profiling, receptor identification across multiple experiments\",\n      \"pmids\": [\"33568815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STAT1 occupies a conserved enhancer element (NRE1) in intron 1 of Nampt in response to IFN-γ, driving Nampt expression; disruption of NRE1 reduces a subset of M1 macrophage genes sensitive to NAMPT activity through glycolytic processes; NRE1 deletion in macrophage lineages reduces anti-tumor immunity and increases tumor burden.\",\n      \"method\": \"ChIP-seq (STAT1 occupancy at NRE1), NRE1 mouse knockout strain, pharmacological NAMPT inhibition, scRNAseq, metabolic glycolysis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-seq identifying regulatory element, unique mouse strain with targeted NRE1 deletion, scRNAseq profiling, multiple orthogonal methods\",\n      \"pmids\": [\"33976173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NAMPT-derived NAD+ fuels PARP1 hyperactivation, which drives parthanatos cell death and skin inflammation; inhibition of NAMPT, PARP1, or NADPH oxidases reduces oxidative stress, keratinocyte DNA damage, and inflammation in zebrafish skin inflammation models; aberrant NAMPT and PARP activity, together with AIFM1 nuclear translocation, were observed in lesional psoriasis patient skin.\",\n      \"method\": \"Genetic and pharmacological inhibition (NAMPT, PARP1, NADPH oxidases), PAR glycohydrolase overexpression, zebrafish models, human organotypic 3D skin models, patient tissue analysis\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and pharmacological interventions across animal and human models; NAMPT-NAD+-PARP1-AIFM1 axis established by convergent evidence\",\n      \"pmids\": [\"34748530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"REV-ERB nuclear receptors (REV-ERBα/β) in cardiomyocytes regulate NAMPT expression via repression of the transcription factor E4BP4; E4BP4 directly represses Nampt through distal cis-regulatory elements; REV-ERB-mediated E4BP4 repression is required for circadian Nampt expression and NAD+ salvage synthesis in heart.\",\n      \"method\": \"Cardiomyocyte-specific Rev-erb double knockout mice, cardiac phenotype analysis, ChIP (E4BP4 binding to Nampt regulatory elements), gene expression analysis\",\n      \"journal\": \"Nature cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific double KO mouse model, direct transcription factor binding to Nampt regulatory elements by ChIP, phenotypic characterization of pathway\",\n      \"pmids\": [\"35036997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-146a directly targets the 3'-UTR of NAMPT mRNA to reduce NAMPT expression; AMPK activators (metformin, AICAR) suppress miR-146a expression at the transcriptional level by promoting IKK phosphorylation and attenuating NF-κB activity, thereby relieving repression of NAMPT and enabling NAD+/SIRT activation.\",\n      \"method\": \"Luciferase reporter assay (miR-146a targeting NAMPT 3'-UTR), miR-146a mimic/inhibitor transfection, AMPK activator treatment, IKK/NF-κB pathway analysis, in vitro and in vivo senescence models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct 3'-UTR targeting confirmed by luciferase assay, convergent pharmacological and genetic approaches, validated in vitro and in vivo\",\n      \"pmids\": [\"35241643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AMPK directly phosphorylates NAMPT at Ser314 in response to ionizing radiation within 30 minutes, increasing NAMPT enzymatic activity by enhancing NAMPT binding to its substrate PRPP; this phosphorylation restores NAD+ levels and facilitates DNA repair and cell viability.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (S314 phosphorylation site), PRPP binding assays, NAD+ measurement, DNA repair assays in irradiated cells\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with mutagenesis of phosphorylation site, substrate binding assay, functional NAD+ rescue; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36196536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAMPT deletion in myeloid cells in colorectal cancer causes HIF-1α destabilization, reducing M2-like TAM polarization and decreasing efferocytosis; this decreased efferocytosis enhances STING signaling and type I IFN-response gene expression, potentiating cytotoxic T cell anti-tumor activity.\",\n      \"method\": \"Myeloid-specific Nampt conditional knockout mice, scRNA-seq, HIF-1α destabilization assay, efferocytosis assay, STING signaling assessment, T cell activity assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — myeloid-specific KO mice, scRNA-seq profiling, multiple mechanistic readouts in vivo; multi-step pathway from NAMPT to HIF-1α to efferocytosis to STING established\",\n      \"pmids\": [\"38308188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAMPT promotes cell survival under oxidative stress via both SIRT1-dependent p53-CD38 pathway and a SIRT1-independent NRF2-PPARα/AMPKα pathway; NAMPT overexpression rescues mitochondrial membrane potential and content under H2O2 treatment via the NRF2-PPARα/AMPKα axis; NRF2 is identified as a downstream target of NAMPT.\",\n      \"method\": \"NAMPT overexpression, SIRT1 inhibition/knockdown, NRF2 pathway analysis, mitochondrial membrane potential assay, cell viability under oxidative stress\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain-of-function with defined phenotypic readout and pathway analysis; single lab, limited mutagenesis confirmation\",\n      \"pmids\": [\"31816398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAMPT deletion in macrophages reduces phagocytic activity due to insufficient NAD+ needed to produce NADPH for the oxidative burst; NMN treatment rescues NADPH levels and restores superoxide generation via NADPH oxidase; NAMPT-deficient mice show impaired dead-cell clearance and prolonged chronic colitis.\",\n      \"method\": \"Myeloid-specific Nampt conditional knockout (Namptf/f LysMCre+/-), phagocytosis assay, NADPH/NAD+ measurement, NADPH oxidase activity, NMN rescue, DSS colitis model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific KO with metabolic rescue by NMN, mechanistic link from NAD+ to NADPH to oxidative burst established in vivo and in vitro\",\n      \"pmids\": [\"35063804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lamin A/C null (Lmna-/-) MEFs show reduced NAMPT expression and attenuated SIRT1 activity; ATAC-seq reveals reduced chromatin accessibility at the Nampt gene promoter in Lmna-/- cells; this is associated with reduced NAD+ levels and mitochondrial dysfunction.\",\n      \"method\": \"Lmna-/- MEF and HGPS fibroblast models, ATAC-seq, NAD+ measurement, SIRT1 activity assay, PGC1α chromatin recruitment analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ATAC-seq providing direct evidence of chromatin regulation of NAMPT promoter; functional consequences established; single lab\",\n      \"pmids\": [\"36099415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CircRNA FEACR directly binds NAMPT protein and enhances its protein stability, increasing NAMPT-dependent SIRT1 expression, which promotes FOXO1 transcriptional activity by reducing FOXO1 acetylation; FOXO1 upregulates FTH1 transcription to inhibit cardiomyocyte ferroptosis.\",\n      \"method\": \"RNA pull-down (FEACR binding to NAMPT), gain/loss-of-function experiments, western blotting, NAMPT stability assay, SIRT1/FOXO1/FTH1 pathway analysis\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA pulldown confirming direct circRNA-NAMPT interaction, pathway cascade established with multiple readouts; single lab\",\n      \"pmids\": [\"37370086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAMPT-containing microvesicles (MVs) shed by radioresistant glioma stem cells transfer NAMPT to radiosensitive cells; the enzymatic activity of NAMPT within recipient cells is necessary to increase intracellular NAD(H) levels and rescue proliferation of irradiated radiosensitive cells.\",\n      \"method\": \"Proteomic analysis of MVs, NAMPT-high MV transfer experiments, NAMPT enzymatic activity requirement assays, NAD(H) measurement in recipient cells, radioresistance phenotype assays\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MV transfer established functionally with NAMPT enzymatic activity requirement confirmed; multiple patient-derived GSC lines; single lab\",\n      \"pmids\": [\"37037593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Low-dose nicotine restores age-related decline in NAMPT activity via SIRT1 binding to NAMPT followed by deacetylation of NAMPT, independent of nicotinic acetylcholine receptors; deacetylation of NAMPT by SIRT1 increases its enzymatic activity and NAD+ synthesis.\",\n      \"method\": \"Co-immunoprecipitation (SIRT1-NAMPT binding), NAMPT enzymatic activity assay, nicotinic receptor blockade, in vivo aging mouse model, 18F-FDG PET imaging\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for binding, enzymatic activity assay for functional consequence, receptor blockade to rule out canonical signaling; single lab\",\n      \"pmids\": [\"36797299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NAMPT-dependent NAD+ control of the molecular clock varies substantially between tissues: brown adipose tissue (BAT) requires NAMPT for clock amplitude; skeletal muscle clock is refractory to NAMPT loss; NAMPT differentially orchestrates oscillation of clock-controlled gene networks and metabolites, including TCA cycle intermediates, in a tissue-specific manner.\",\n      \"method\": \"Tissue-specific Nampt knockout mouse models, transcriptomic analysis, metabolomics (TCA cycle intermediates), circadian amplitude measurements, cold challenge assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO models, transcriptomics and metabolomics across multiple tissues, functional circadian and metabolic phenotyping\",\n      \"pmids\": [\"36996103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAMPT inhibition in macrophages causes HIF-1α destabilization, directly linking NAMPT-dependent NAD+ production to HIF-1α stability and M2-like macrophage polarization.\",\n      \"method\": \"Myeloid-specific Nampt KO, HIF-1α protein stability assay, macrophage polarization markers\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — specific KO with defined molecular readout; HIF-1α destabilization identified but mechanism linking NAD+ to HIF-1α stability not fully resolved; single lab\",\n      \"pmids\": [\"38308188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Small molecule NAMPT positive allosteric modulators (N-PAMs) bind to the 'rear channel' of NAMPT, increasing enzyme activity and alleviating feedback inhibition by NAM and NAD+; binding affinity to the rear channel correlates directly with potency for enzyme activation, and activation translates to elevated cellular NAD+.\",\n      \"method\": \"Structure-activity relationship study (>70 compounds), rear channel binding affinity assays, enzymatic activity assays, cellular NAD+ measurement\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic reconstitution with binding site characterization; structure-activity correlation establishes allosteric mechanism; single lab\",\n      \"pmids\": [\"38096366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAMPT inhibition in macrophages reduces their efferocytosis activity due to insufficient NAD+-derived NADPH for oxidative burst; decreased efferocytosis activates STING signaling promoting type I IFN response genes.\",\n      \"method\": \"Myeloid-specific Nampt KO, efferocytosis assay, NADPH measurement, STING pathway assays, IFN-response gene expression\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific KO linking NAMPT/NAD+/NADPH to efferocytosis and downstream STING activation; multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"38308188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PBEF (NAMPT) induces VEGF secretion by amniotic epithelial cells and increases VEGFR2 expression in placental amniotic epithelial cells (but not reflected AEC); PBEF combined with VEGF increases permeability of the placental amnion, measured by DCF transfer across amnion explants.\",\n      \"method\": \"Primary human amniotic epithelial cell (AEC) cultures, VEGF ELISA, VEGFR2 expression analysis, amnion permeability assay with DCF tracer\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct functional assay of amnion permeability with pharmacological treatment; receptor upregulation by PBEF established; single lab\",\n      \"pmids\": [\"23151382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NAMPT inhibits progesterone secretion in hen granulosa cells via its enzymatic (NAMPT) activity; recombinant NAMPT (100 ng/ml) reduces basal and IGF1-induced progesterone secretion and decreases STAR and HSD3B protein levels and MAPK3/1 phosphorylation; the effect is abolished by FK866, confirming enzymatic activity dependence.\",\n      \"method\": \"Primary hen granulosa cell cultures, FK866 enzymatic inhibition, progesterone ELISA, western blotting for STAR/HSD3B, MAPK3/1 phosphorylation assay\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FK866 enzymatic inhibition confirms mechanism dependency; multiple signaling readouts; single lab with avian model\",\n      \"pmids\": [\"25918435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NAMPT inhibition in hypothalamic neurons by ICV-administered FK866 completely ablates fasting- and ghrelin-induced increases in food intake without causing malaise; NAMPT inhibition in primary hypothalamic neurons reduces NAD+, increases reactive oxygen species, affects mitochondrial respiration, and alters expression of Agrp and Pomc.\",\n      \"method\": \"ICV FK866 administration, metabolic cage food intake measurement, primary hypothalamic neuron FK866 treatment, ROS measurement, mitochondrial respiration assay, Agrp/Pomc gene expression\",\n      \"journal\": \"Acta physiologica (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with defined behavioral and molecular readouts in vivo and in vitro; single lab\",\n      \"pmids\": [\"31900990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAMPT promotes IFNγ production by CD4+ T cells in lupus nephritis by supporting aerobic glycolysis and mitochondrial respiration through NAD+ production; NAMPT promotes translational efficiency of Ifng mRNA in CD4+ T cells; FK866 or siRNA knockdown suppresses IFNγ production and reduces kidney damage in lupus mice.\",\n      \"method\": \"NAMPT inhibition by FK866 and siRNA in CD4+ T cells from LN patients and MRL/lpr mice, glycolysis/mitochondrial respiration assay, translational efficiency assay, in vivo siRNA delivery with kidney damage scoring\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — convergent pharmacological and genetic inhibition with defined metabolic and translational readouts; in vivo and patient cell validation; single lab\",\n      \"pmids\": [\"36146932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAMPT inhibition by FK866 enhances acetylation of LDHA in cells, reducing LDHA activity and decreasing lactate production; NAMPT functions upstream of SIRT2 to regulate LDHA acetylation status, forming a Nampt/SIRT2/LDHA pathway that controls lactate production in granulosa cells.\",\n      \"method\": \"Co-immunoprecipitation (LDHA acetylation state), FK866 NAMPT inhibition, SIRT2 inhibition, NAMPT inhibitor and NMN supplementation in PCOS rat model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for acetylation state, pharmacological pathway dissection; in vivo and in vitro convergent evidence; single lab\",\n      \"pmids\": [\"39489197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NAMPT depletion in hippocampal CA1 neurons causes mitochondrial swelling and decreased mitochondrial number, cognitive deficiency, and increased intracellular Aβ aggregation; in primary neurons, FK866 inhibition of NAMPT drops mitochondrial membrane potential and decreases neurite branching in a dose-dependent manner.\",\n      \"method\": \"Hippocampus-specific Nampt KO (rAAV-hSyn-Cre), transmission electron microscopy, immunofluorescence, FK866 inhibition in primary neurons, mitochondrial membrane potential assay\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — neuron-specific KO with ultrastructural and functional phenotyping; pharmacological confirmation in primary cells; single lab\",\n      \"pmids\": [\"36441480\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NAMPT is a dimeric type II phosphoribosyltransferase that catalyzes the rate-limiting conversion of nicotinamide to nicotinamide mononucleotide (NMN) using phosphoribosyl pyrophosphate (PRPP) and ATP—a reaction allosterically regulated by a rear-channel binding site and post-translationally controlled by AMPK-mediated Ser314 phosphorylation and SIRT1-mediated deacetylation; by sustaining cellular and systemic NAD+ pools, intracellular NAMPT governs the activity of NAD+-dependent enzymes (SIRT1, PARP1, CD38) to control insulin secretion in beta cells, IFNγ production in T cells, glycolysis-linked macrophage effector functions (phagocytosis, M1/M2 polarization via HIF-1α), neuronal mitochondrial integrity, and circadian metabolic oscillations in a tissue-specific manner; extracellular NAMPT functions as a cytokine by directly ligating TLR4 (via a structurally distinct loop region S402–N412) to activate NF-κB signaling, and can also signal through Ccr5 on muscle stem cells to promote their proliferation, while its pro-inflammatory enzymatic activity drives MAPK–NF-κB cascades and PARP1-mediated parthanatos; NAMPT expression is transcriptionally regulated by STAT1 (via a conserved intronic element NRE1 induced by IFN-γ), by the circadian REV-ERB/E4BP4 axis, and post-transcriptionally by miR-146a targeting its 3'-UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NAMPT is the rate-limiting enzyme of the mammalian NAD+ salvage pathway, a dimeric type II phosphoribosyltransferase that converts nicotinamide to nicotinamide mononucleotide (NMN) using PRPP, sustaining cellular and systemic NAD+ pools that govern diverse metabolic and inflammatory programs [#0, #2]. By providing the NAD+ that drives NAD+-dependent enzymes, intracellular NAMPT controls glucose-stimulated insulin secretion in pancreatic islets [#1], supports SIRT1- and PARP1-dependent signaling [#7], fuels macrophage glycolysis, HIF-1\\u03b1 stabilization, and the NADPH-dependent oxidative burst needed for phagocytosis and efferocytosis [#21, #27, #29], promotes CD4+ T cell IFN\\u03b3 production through aerobic glycolysis and Ifng translation [#33], and maintains neuronal mitochondrial integrity [#35]. The enzyme's activity is regulated allosterically through a rear-channel binding site that relieves NAM/NAD+ feedback inhibition [#28] and post-translationally by AMPK-mediated Ser314 phosphorylation, which enhances PRPP binding to restore NAD+ for DNA repair [#18], and by SIRT1-mediated deacetylation that boosts catalytic activity [#25]. NAMPT also functions extracellularly: hepatocytes and glucose-stimulated islets secrete an enzymatically active dimeric form [#3, #8], which acts as a pro-inflammatory mediator that requires its enzymatic activity to drive MAPK\\u2013NF-\\u03baB cascades in macrophages and synovial fibroblasts [#6, #11], directly ligates TLR4 via a protruding S402\\u2013N412 loop to activate NF-\\u03baB [#10], signals through Ccr5 on muscle stem cells to drive proliferation [#13], and fuels PARP1 hyperactivation and parthanatos in skin inflammation [#15]. NAMPT expression is transcriptionally controlled by STAT1 acting at the intronic NRE1 enhancer in response to IFN-\\u03b3 [#14] and by the circadian REV-ERB/E4BP4 axis [#16], with NAMPT-dependent NAD+ in turn driving tissue-specific circadian metabolic oscillations [#26]; expression is also tuned post-transcriptionally by miR-146a targeting its 3'-UTR [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing the enzyme class and catalytic architecture was the foundational question; the crystal structure defined NAMPT as a dimeric type II phosphoribosyltransferase and revealed how it synthesizes NMN from nicotinamide.\",\n      \"evidence\": \"X-ray crystallography with and without NMN product\",\n      \"pmids\": [\"16783373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo regulation of the enzyme\", \"Allosteric and post-translational control sites not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Whether NAMPT was rate-limiting for NAD+ biosynthesis and physiologically essential was unresolved; haplodeficiency and chemical inhibition causing NAD+ and insulin-secretion defects rescuable by NMN established its role as the rate-limiting salvage enzyme.\",\n      \"evidence\": \"Genetic haplodeficiency mouse, chemical inhibition, glucose-stimulated insulin secretion, NMN rescue, enzymatic assays\",\n      \"pmids\": [\"17983582\", \"17268245\", \"16783373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions not dissected\", \"Did not address extracellular function\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether secreted NAMPT retained catalytic function was open; hepatocyte-secreted NAMPT was shown to be dimeric and enzymatically active, establishing an extracellular pool comparable to the intracellular form.\",\n      \"evidence\": \"Size exclusion chromatography and enzymatic assays on HepG2 and primary hepatocyte secretions\",\n      \"pmids\": [\"19912992\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Secretion mechanism not defined\", \"Physiological function of extracellular pool not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Early functional studies asked whether NAMPT/PBEF acts in inflammation; reciprocal gain/loss-of-function linked it to IL-8 secretion, IL-1\\u03b2-mediated permeability, and mitochondrial/oxidative-stress interactions in pulmonary cells.\",\n      \"evidence\": \"Overexpression and siRNA knockdown in A549/HPAEC, cytokine and permeability assays, Co-IP with ND1/ferritin/IFITM3\",\n      \"pmids\": [\"18996492\", \"18486613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction mechanism with mitochondrial partners unresolved\", \"Enzymatic vs cytokine activity not separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether the pro-inflammatory and pro-tumor actions of NAMPT require its catalytic activity was tested; pharmacological/genetic inhibition with NAD+/NMN rescue confirmed enzymatic dependence in myeloma growth, MAPK\\u2013NF-\\u03baB inflammation, and glucose-dependent islet secretion.\",\n      \"evidence\": \"APO866/FK866 inhibition, siRNA, NAD+/NMN rescue, PARP-1/SIRT-1 assays, xenografts, pathway inhibitors, secretion assays\",\n      \"pmids\": [\"23435312\", \"21327328\", \"22767598\", \"23536823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating extracellular signaling not yet identified\", \"Distinction between NMN production and direct ligand activity incomplete\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The receptor for extracellular NAMPT cytokine activity was unknown; computational and functional analysis identified direct TLR4 ligation via an LPS-like S402\\u2013N412 loop driving NF-\\u03baB and lung injury.\",\n      \"evidence\": \"Computational structural analysis, TLR4/NF-\\u03baB reporter assays, VILI mouse model\",\n      \"pmids\": [\"26272519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding partly inferred computationally\", \"Relationship between TLR4 ligation and enzymatic activity unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"How NAMPT couples to specific cellular outcomes was addressed across systems; macrophage-secreted NAMPT was found to signal through Ccr5 on muscle stem cells, IFN-\\u03b3/STAT1 to drive Nampt via the NRE1 enhancer for M1 macrophage glycolysis and anti-tumor immunity, REV-ERB/E4BP4 to set circadian Nampt expression, and NAMPT-derived NAD+ to fuel PARP1-driven parthanatos in skin.\",\n      \"evidence\": \"Zebrafish injury/live imaging, scRNAseq, ChIP-seq, NRE1 and Rev-erb KO mice, PARP1/NADPH-oxidase inhibition, human skin models\",\n      \"pmids\": [\"33568815\", \"33976173\", \"35036997\", \"34748530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ccr5 ligation mechanism distinct from enzymatic NAD+ not fully defined\", \"How NAD+ flux selectively tunes specific effector genes incomplete\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The post-transcriptional and post-translational control of NAMPT, and its downstream NAD+-dependent effector axes, were dissected; AMPK Ser314 phosphorylation enhances PRPP binding and DNA repair, miR-146a represses NAMPT via its 3'-UTR, lamin A/C and circRNA FEACR modulate NAMPT expression/stability, and myeloid NAMPT controls HIF-1\\u03b1, efferocytosis, STING, and oxidative burst.\",\n      \"evidence\": \"In vitro kinase assay/S314 mutagenesis, luciferase 3'-UTR assay, ATAC-seq, RNA pull-down, myeloid-specific KO mice, scRNA-seq, NMN rescue, mitochondrial/SIRT1 assays\",\n      \"pmids\": [\"36196536\", \"35241643\", \"36099415\", \"37370086\", \"38308188\", \"35063804\", \"31816398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking NAD+ to HIF-1\\u03b1 stability not fully resolved\", \"Integration of multiple regulatory inputs in vivo unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Allosteric activation and SIRT1 feedback regulation were defined; rear-channel positive allosteric modulators relieve NAM/NAD+ feedback inhibition, and SIRT1 binds and deacetylates NAMPT to raise its activity, while tissue-specific NAD+ control of the clock was mapped.\",\n      \"evidence\": \"SAR study with rear-channel binding assays, Co-IP, enzymatic assays, tissue-specific KO mice, transcriptomics/metabolomics\",\n      \"pmids\": [\"38096366\", \"36797299\", \"36996103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of SIRT1-NAMPT interaction not solved\", \"Why some tissues are refractory to NAMPT loss unexplained\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"NAMPT-controlled deacetylation of metabolic enzymes was added to the model, with the Nampt/SIRT2/LDHA axis shown to regulate lactate production.\",\n      \"evidence\": \"Co-IP for LDHA acetylation, FK866/SIRT2 inhibition, NMN supplementation, PCOS rat model\",\n      \"pmids\": [\"39489197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs NAD+-dependent regulation of SIRT2 not separated\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the enzymatic (NAD+-generating) and non-enzymatic cytokine/receptor-ligand functions of extracellular NAMPT are mechanistically partitioned, and how a single secreted protein engages distinct receptors (TLR4, Ccr5) in different tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of NAMPT bound to TLR4 or Ccr5\", \"Secretion/export route of intracellular NAMPT undefined\", \"Relative contribution of enzymatic vs ligand activity in vivo not quantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 28]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [10, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 21]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 8, 10, 13]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 14, 21, 33]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 10, 11]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [16, 26]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TLR4\", \"Ccr5\", \"SIRT1\", \"PARP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}