{"gene":"NPY1R","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2003,"finding":"Genetic redundancy between NPY1R (Y1) and NPY5R (Y5) receptor signaling in NPY-mediated control of food intake: mice lacking either Npy1r or Npy5r still showed full feeding and obesity responses to chronic intracerebroventricular NPY infusion, indicating that neither receptor alone is solely required when the other is present.","method":"Chronic ICV NPY infusion in Npy1r and Npy5r knockout mice; measurement of food intake, fat pad weight, plasma insulin/leptin/corticosterone, and hypothalamic NPY/POMC mRNA","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with multiple orthogonal physiological and molecular readouts, replicated across two receptor KO lines","pmids":["14525913"],"is_preprint":false},{"year":2018,"finding":"Conditional inactivation of Npy1r in Y5R-containing neurons (Npy1rY5R-/- mice) impairs behavioral flexibility (reversal learning) and causes decreased serotonergic fiber density and increased baseline neural activity (c-Fos) in the orbitofrontal cortex; acute escitalopram treatment restores OFC activity and behavioral flexibility, placing Y1R upstream of serotonergic tone in OFC circuits.","method":"Conditional KO mouse model (Npy1rY5R-/- mice); Morris water maze and water T-maze reversal learning; immunohistochemical quantification of c-Fos and 5-HT fibers in OFC; pharmacological rescue with SSRI escitalopram","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with multiple orthogonal behavioral and immunohistochemical readouts and pharmacological rescue in a single lab","pmids":["29353053"],"is_preprint":false},{"year":2020,"finding":"NPY1R signaling in the medial prefrontal cortex enhances GABAergic inhibitory currents: maternally deprived mice show upregulated Npy1r expression and increased inhibitory synaptic inputs to mPFC neurons, and pharmacological blockade of NPY1R reduces GABAergic currents specifically in these animals.","method":"Maternal separation protocol in mice; RNAseq for gene expression changes; electrophysiological recordings (mPFC) with NPY1R pharmacological blockade; dendritic morphology analysis","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — electrophysiological recordings with receptor blockade plus RNAseq and morphological analysis in a single lab, multiple orthogonal methods","pmids":["32492699"],"is_preprint":false},{"year":2020,"finding":"Conditional inactivation of Npy1r in limbic excitatory neurons produces sex-specific metabolic and behavioral phenotypes: male Npy1rrfb mice show HPA hyperactivation, anxiety, reduced body weight and adiposity; female Npy1rrfb mice show anxiety but no HPA or body weight changes, instead accumulating more WAT with compensatory reduction of AgRP in the arcuate nucleus, indicating estrogen-dependent relay that maintains homeostasis.","method":"Conditional KO mice (Npy1rrfb); behavioral tests; HPA axis hormone measurements; fat pad weighing; plasma leptin; AgRP immunoreactivity in arcuate nucleus; Npy1r mRNA quantification by brain region and sex","journal":"Hormones and behavior","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional KO with multiple physiological and neuroendocrine readouts across both sexes in a single lab","pmids":["32755609"],"is_preprint":false},{"year":2020,"finding":"The lncRNA MCM3AP-AS1 recruits DNMT1/DNMT3A/DNMT3B to the NPY1R promoter, promoting its methylation and transcriptional silencing, thereby activating the MAPK pathway to drive prostate cancer cell proliferation, invasion, and migration; NPY1R overexpression reverses MCM3AP-AS1-driven tumor growth in vivo.","method":"RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation (ChIP), methylation-specific PCR; NPY1R overexpression rescue; xenograft tumor model; scratch/Transwell/EdU/flow cytometry assays","journal":"Molecular therapy. Nucleic acids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RIP, pulldown, ChIP, MSP, in vivo rescue) in a single lab; mechanistic link between lncRNA-DNMT recruitment and NPY1R promoter methylation is well-supported","pmids":["32193153"],"is_preprint":false},{"year":2022,"finding":"NPY1R mediates inhibitory effects of NPY on estradiol-stimulated growth of ER+ breast cancer cells: NPY treatment reduces estradiol-stimulated cell growth, and this effect is reversed by the NPY1R antagonist BIBP-3226.","method":"NPY treatment with/without NPY1R antagonist BIBP-3226 in ER+ BC cell lines; cell growth assays; xenograft models; endocrine therapy resistance cell models in vitro and in vivo","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological antagonist rescue in multiple cell and xenograft models, single lab, two orthogonal experimental systems","pmids":["35121782"],"is_preprint":false},{"year":2023,"finding":"Within the spinal dorsal horn, NPY1R interneurons (Y1-INs) segregate into three largely non-overlapping subpopulations (Grp/Npy1r, Npff/Npy1r, Cck/Npy1r); specifically, Grp/Npy1r interneurons are necessary for NPY-mediated analgesia in neuropathic pain — intrathecal Y1 agonist reduces neuropathic hypersensitivity in mice lacking Npy1r in CCK- and NPFF-INs but not in GRP-INs.","method":"Fluorescence in situ hybridization (FISH) to characterize Y1-IN subpopulations in mice, non-human primates, and humans; chemogenetic inhibition of Npff/Npy1r-INs; conditional deletion of Npy1r from CCK-INs and NPFF-INs; intrathecal Y1 agonist [Leu31,Pro34]-NPY; neuropathic pain behavioral assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic deletion with pharmacological rescue across multiple neuron-type-specific KO lines, cross-species FISH validation in primates and humans","pmids":["37824208"],"is_preprint":false},{"year":2024,"finding":"NPY1R forms heteroreceptor complexes with GALR2 and with TrkB in the dentate gyrus of the hippocampus; co-activation of NPY1R and GALR2 increases co-localization signals and neuroblast proliferation, and co-administration of NPY1R agonist with ketamine increases NPY1R-TrkB complex formation and BDNF expression, associated with enhanced neurogenesis and memory consolidation.","method":"In situ proximity ligation assay (PLA) for receptor co-localization; intracerebroventricular or intranasal drug administration; PCNA and DCX immunohistochemistry for neurogenesis; object-in-place memory task","journal":"Frontiers in cellular neuroscience / Cells / Expert opinion on therapeutic targets","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — PLA co-localization consistent across multiple studies from the same group; interaction not yet confirmed by co-IP or reconstitution, but replicated with two different receptor pairs","pmids":["38425430","38667284","38622072","38572811"],"is_preprint":false},{"year":2024,"finding":"NPY1R-TrkB and NPY1R-GALR2 heteroreceptor complexes in the ventral hippocampus are disrupted by ICV siRNA knockdown of NPY1R; this disruption does not alter hippocampal neurogenesis (PCNA counts), BDNF expression, or depressive-like behavior (forced swim test), indicating compensatory mechanisms that preserve plasticity despite receptor complex loss.","method":"ICV Accell siRNA knockdown of NPY1R; in situ PLA for NPY1R-GALR2 and NPY1R-TrkB complexes; PCNA immunolabeling; BDNF immunostaining; forced swim test","journal":"Journal of psychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with PLA validation of complex disruption and multiple functional readouts; single lab, confirms negative result for neurogenesis/behavior","pmids":["41307298"],"is_preprint":false},{"year":2025,"finding":"NPY1R exerts a cell-autonomous brake on adipocyte lipolysis: NPY dose-dependently attenuates lipolysis and cAMP signaling in primary human subcutaneous adipocytes; NPY1R expression correlates positively with adiposity and decreases after weight loss, with reduced NPY1R associated with enhanced beta-adrenergic-induced lipolysis.","method":"Single nuclei RNA sequencing of scWAT before/after lifestyle intervention; pharmacological NPY treatment in primary human adipocytes; cAMP signaling assays; meta-analysis of 23 clinical studies","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro functional assay in primary human adipocytes with cAMP readout, supported by snRNAseq and replicated across 23-study meta-analysis","pmids":["41412283"],"is_preprint":false},{"year":2025,"finding":"NPY/NPY1R signaling promotes pancreatic cancer metastasis to the liver: pancreas-specific and whole-body Npy1r knockout, as well as pharmacological inhibition with BIBO3304, significantly reduces liver metastasis in autochthonous KPR172HC mouse models and in an intrasplenic metastasis model; BIBO3304 reduces cancer cell migration on cell-derived matrices.","method":"Genetically engineered autochthonous KPR172HC mouse model with pancreas-specific and whole-body Npy1r KO; intrasplenic metastasis model; NPY1R antagonist BIBO3304 treatment; cell migration assays on cell-derived matrices","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in autochthonous model plus pharmacological inhibition in independent intrasplenic model, replicated across multiple experimental approaches in one study","pmids":["40073121"],"is_preprint":false},{"year":2025,"finding":"NPY1R identifies a colon-specific LGR5+ stem cell population in the middle and distal colorectum; selective dysregulation of Wnt signaling in NPY1R+ stem cells using CreERT2 lines drives colon cancer initiation predominantly in the rectum, establishing NPY1R+ stem cells as a source of colorectal cancer.","method":"CreERT2 mouse lines targeting NPY1R+ cells; conditional Wnt signaling activation; combination with oncogenic Kras and Trp53 loss; histological and cancer progression analysis","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic lineage-specific targeting with CreERT2 in multiple genetic backgrounds, with tumor initiation and progression as functional readout","pmids":["40897804"],"is_preprint":false},{"year":2025,"finding":"UHRF1 binds the NPY1R promoter, promotes its methylation, and suppresses NPY1R transcription in intestinal epithelial cells; UHRF1 deficiency upregulates NPY1R, which attenuates cAMP/PKA/CREB signaling, enhances NF-κB activation and proinflammatory IL-6/NLRP3 expression, and compromises intestinal epithelial barrier integrity.","method":"UHRF1 KO mouse model (intestinal epithelial-specific); human cell models; ChIP for UHRF1 binding to NPY1R promoter; methylation analysis; cAMP/PKA/CREB and NF-κB signaling assays; ELISA for IL-6; barrier integrity assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP validation of UHRF1-NPY1R promoter interaction, KO mouse model with multiple downstream pathway measurements in a single study","pmids":["41657307"],"is_preprint":false},{"year":2025,"finding":"MOR (μ-opioid receptor, Oprm1) is co-expressed in ~21% of NPY1R+ interneurons in the spinal dorsal horn; MOR activation in NPY1R+ interneurons is required for morphine analgesia — conditional deletion of Oprm1 from NPY1R+ neurons impairs morphine analgesia. Intrathecal NPY synergistically enhances morphine analgesia via NPY1R, an effect abolished by NPY1R antagonism or Npy1r knockout. NPY1R+ neuron hyperexcitability induced by inflammation is suppressed by morphine.","method":"In situ hybridization; conditional Oprm1 KO in NPY1R+ neurons (AAV-Npy1r-Cre-EGFP); chemogenetic approaches; intrathecal NPY +/- NPY1R antagonist; Npy1r-/- mice; whole-cell electrophysiology of spinal cord slices; multiple pain models","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (conditional KO, chemogenetics, pharmacology, electrophysiology, ISH) across multiple pain models in a single comprehensive study","pmids":["41738433"],"is_preprint":false},{"year":2025,"finding":"NPY1R is phosphorylated by tyrosine kinase (TK), and TK inhibition (TKI) suppresses NPY1R-mediated promotion of vascular smooth muscle cell phenotypic transition (contractile-to-synthetic), inflammatory response, and M1 macrophage polarization in an intracranial aneurysm mouse model; macrophage ablation abolished NPY1R overexpression-mediated promotion of aneurysm formation.","method":"Co-immunoprecipitation (Co-IP) validating TK-NPY1R interaction; NPY1R overexpression in IA mouse model; TKI treatment; flow cytometry for immune cell populations; ELISA for inflammatory factors; HE staining","journal":"Neuropeptides","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for TK-NPY1R interaction, in vivo KO and pharmacological rescue; single lab with multiple readouts but abstract provides limited mechanistic detail on the kinase identity","pmids":["39353356"],"is_preprint":false},{"year":2025,"finding":"NPY1R activates PI3K/AKT/mTOR (PAM) signaling to support osteogenic differentiation: NPY1R suppression reduced osteogenic capacity of iPSCs, and PAM pathway inhibition with LY294002 decreased osteogenic activity; NPY1R and PAM pathway activation were confirmed in vivo in a rat periodontitis model during bone repair.","method":"Transcriptomic profiling of iPSC osteogenic differentiation; NPY1R knockdown; LY294002 PAM pathway inhibition; in vivo rat periodontitis model with NPY1R and pathway marker analysis","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, transcriptomics plus pharmacological inhibition without direct mechanistic linking of NPY1R to PI3K activation (no binding or signaling reconstitution)","pmids":["41268237"],"is_preprint":false},{"year":2025,"finding":"NPY1R overexpression in ovarian granulosa cells activates p-CREB signaling, promotes IL-6 and NLRP3 expression, induces ROS accumulation, ferroptosis, and mitochondrial dysfunction, accelerating ovarian senescence; NPY1R antagonist BIBO 3304 reverses these phenotypes in vivo.","method":"In vivo NPY1R agonist ([Leu31,Pro34]-NPY) and antagonist (BIBO 3304) administration in mice; transcriptome sequencing of aged human granulosa cells; ROS and mitochondrial assays; estrous cycle monitoring; follicular development analysis; CREB, IL-6, NLRP3 measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological agonist/antagonist in vivo rescue with multiple mechanistic readouts (CREB, NLRP3, ROS, ferroptosis) plus human transcriptomics, single lab","pmids":["42262763"],"is_preprint":false},{"year":2025,"finding":"Nobiletin (NOB) directly binds NPY1R (confirmed by molecular docking) and reduces Npy1r overexpression in pancreatic β-cells; NOB mitigates NPY1R-mediated β-cell insulin secretion deficiency by activating the RORs/Bmal1-YAP clock-modulatory pathway, suppressing YAP and activating Bmal1, thereby restoring insulin secretion in T2DM mouse models.","method":"Molecular docking for NOB-NPY1R interaction; Bmal1::Luc bioluminescence rhythmicity in MIN6 cells; NPY1R antagonist (BMS 193885) and palmitic acid/NPY interventions; T2DM mouse models (HFD+STZ and acute NPY hyperglycemia); Npy1r expression analysis in β-cells","journal":"Molecular nutrition & food research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — molecular docking plus cell-based functional assays and two in vivo models; single lab; direct binding not confirmed by biophysical assay beyond docking","pmids":["40913544"],"is_preprint":false},{"year":2025,"finding":"In the gut, PYY-expressing colonic L-cells release PYY which acts on NPY1R-expressing enterochromaffin (EC) cells to enhance serotonin release and gut pain sensitivity in a female-specific estrogen-responsive paracrine circuit.","method":"Preprint: identification of NPY1R expression on EC cells; estrogen receptor alpha signaling manipulation; PYY/NPY1R pharmacological dissection in colonic circuit; gut pain behavioral assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, paracrine mechanism inferred from pharmacological and receptor expression studies without direct reconstitution of NPY1R signaling in EC cells","pmids":[],"is_preprint":true}],"current_model":"NPY1R is a GPCR that, upon activation by NPY or PYY, inhibits cAMP signaling in multiple cell types (adipocytes, β-cells, neurons) and mediates NPY's orexigenic, analgesic, anxiolytic, and metabolic effects; in the spinal dorsal horn, NPY1R+ interneurons (particularly the Grp/Npy1r subset) are necessary for NPY-mediated analgesia and interact with MOR signaling to modulate morphine efficacy; in the brain, NPY1R enhances GABAergic inhibitory tone, forms heteroreceptor complexes with GALR2 and TrkB in the hippocampus to support neuroplasticity, and its limbic expression regulates HPA axis activity, anxiety, and aggression in a sex-dependent manner; in peripheral tissues, NPY1R is regulated epigenetically by UHRF1-mediated promoter methylation and by lncRNA-DNMT recruitment, suppresses lipolysis in adipocytes via cAMP/PKA, drives vascular smooth muscle cell phenotypic switching when phosphorylated by tyrosine kinase, marks a distinct LGR5+ colorectal stem cell population that serves as a cancer origin, and its NPY/NPY1R axis promotes pancreatic cancer metastasis."},"narrative":{"mechanistic_narrative":"NPY1R (Y1 receptor) is a neuropeptide Y/peptide YY receptor that acts as a cell-autonomous brake on cAMP signaling and, through this and downstream cascades, governs metabolism, nociception, neuroplasticity, and stress physiology [PMID:41412283]. In adipocytes NPY signaling through NPY1R dose-dependently attenuates lipolysis and cAMP signaling, with receptor abundance tracking adiposity such that reduced NPY1R licenses beta-adrenergic lipolysis [PMID:41412283]; an analogous cAMP/PKA/CREB-restraining role operates in intestinal epithelium, where NPY1R induction limits NF-κB-driven IL-6/NLRP3 inflammation and supports barrier integrity [PMID:41657307]. In the spinal dorsal horn, NPY1R-expressing interneurons partition into Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r subsets, with the Grp/Npy1r population specifically required for NPY-mediated analgesia in neuropathic pain [PMID:37824208]; a subset of these neurons co-express the μ-opioid receptor, and NPY acting through NPY1R synergistically enhances morphine analgesia [PMID:41738433]. In limbic and cortical circuits, NPY1R enhances GABAergic inhibitory tone in the medial prefrontal cortex [PMID:32492699], positions upstream of serotonergic tone in the orbitofrontal cortex to support behavioral flexibility [PMID:29353053], and regulates HPA axis activity, anxiety, and body weight in a sex-dependent manner [PMID:32755609]; in the hippocampus it forms heteroreceptor complexes with GALR2 and TrkB linked to neuroblast proliferation and memory [PMID:38425430, PMID:38667284, PMID:38622072, PMID:38572811]. NPY1R transcription is epigenetically silenced by promoter methylation driven by UHRF1 [PMID:41657307] and by lncRNA MCM3AP-AS1-mediated DNMT recruitment [PMID:32193153]. The NPY/NPY1R axis drives cancer phenotypes, promoting pancreatic cancer liver metastasis [PMID:40073121] and marking an LGR5+ colorectal stem cell population that serves as a cancer cell of origin [PMID:40897804].","teleology":[{"year":2003,"claim":"Established whether NPY1R is singularly required for NPY's orexigenic effect, revealing functional redundancy with the Y5 receptor.","evidence":"Chronic ICV NPY infusion in Npy1r and Npy5r knockout mice with feeding, adiposity, and hypothalamic mRNA readouts","pmids":["14525913"],"confidence":"High","gaps":["Does not resolve receptor-specific contributions when both are functional","No cell-type or circuit resolution of the redundancy"]},{"year":2018,"claim":"Placed NPY1R upstream of serotonergic tone in cortical circuits controlling behavioral flexibility, linking the receptor to executive function rather than only feeding.","evidence":"Conditional Npy1r KO in Y5R neurons; reversal learning, OFC c-Fos and 5-HT fiber immunohistochemistry, SSRI rescue","pmids":["29353053"],"confidence":"High","gaps":["Mechanism connecting NPY1R signaling to serotonergic fiber density unknown","Receptor-intrinsic signaling step not defined"]},{"year":2020,"claim":"Defined NPY1R's circuit-level action in limbic/cortical neurons, showing it enhances GABAergic inhibition and controls HPA/anxiety/metabolic outputs sex-dependently.","evidence":"Maternal separation and conditional KO mice; mPFC electrophysiology with receptor blockade, RNAseq, neuroendocrine and adiposity measurements","pmids":["32492699","32755609"],"confidence":"High","gaps":["Molecular basis of estrogen-dependent sex divergence not resolved","Direct receptor signaling to GABAergic transmission not reconstituted"]},{"year":2020,"claim":"Identified epigenetic silencing of NPY1R by lncRNA-directed DNMT recruitment as a driver of prostate cancer, framing NPY1R as a methylation-controlled tumor suppressor in this context.","evidence":"RIP, RNA pull-down, ChIP, methylation-specific PCR, NPY1R overexpression rescue, and xenografts in prostate cancer cells","pmids":["32193153"],"confidence":"Medium","gaps":["How NPY1R loss feeds MAPK activation mechanistically unclear","Single tumor-type model"]},{"year":2022,"claim":"Showed NPY1R mediates NPY's growth-inhibitory effect on estrogen-driven breast cancer, extending its tumor-modulating role to hormone-responsive cancers.","evidence":"NPY treatment with NPY1R antagonist BIBP-3226 in ER+ breast cancer cells and xenografts","pmids":["35121782"],"confidence":"Medium","gaps":["Downstream signaling linking NPY1R to growth inhibition undefined","Single antagonist used"]},{"year":2023,"claim":"Resolved NPY1R spinal interneurons into molecular subtypes and pinpointed the Grp/Npy1r population as necessary for NPY analgesia, giving cell-type precision to the receptor's antinociceptive role.","evidence":"Cross-species FISH, chemogenetic inhibition, subtype-specific conditional Npy1r deletion, intrathecal Y1 agonist in neuropathic pain models","pmids":["37824208"],"confidence":"High","gaps":["Circuit output of Grp/Npy1r neurons not fully mapped","Signaling within these interneurons not characterized"]},{"year":2024,"claim":"Demonstrated NPY1R participates in heteroreceptor complexes with GALR2 and TrkB supporting hippocampal neurogenesis and memory, but follow-up knockdown showed plasticity is preserved via compensation, qualifying the functional weight of these complexes.","evidence":"In situ proximity ligation assay, ICV/intranasal drug administration, neurogenesis markers and memory tasks; ICV siRNA knockdown with PLA and behavioral readouts","pmids":["38425430","38667284","38622072","38572811","41307298"],"confidence":"Medium","gaps":["Complexes shown only by PLA, not co-IP or reconstitution","Compensatory mechanisms preserving plasticity unidentified"]},{"year":2025,"claim":"Established the cell-autonomous, cAMP-restraining mechanism of NPY1R in human adipocytes and intestinal epithelium, unifying its metabolic and anti-inflammatory actions through cAMP/PKA/CREB suppression.","evidence":"Primary human adipocyte lipolysis and cAMP assays with snRNAseq and clinical meta-analysis; intestinal epithelial UHRF1 KO mouse with cAMP/PKA/CREB and NF-κB signaling readouts","pmids":["41412283","41657307"],"confidence":"High","gaps":["Coupling to specific Gi/o subtypes not detailed in corpus","Tissue-specific effector divergence not fully mapped"]},{"year":2025,"claim":"Showed UHRF1-mediated promoter methylation as a second epigenetic axis controlling NPY1R, controlling intestinal inflammation and barrier function.","evidence":"Intestinal epithelial-specific UHRF1 KO mouse, ChIP, methylation analysis, downstream signaling and barrier assays","pmids":["41657307"],"confidence":"High","gaps":["Stimuli regulating UHRF1 recruitment to NPY1R unknown","Relationship to the lncRNA-DNMT axis not integrated"]},{"year":2025,"claim":"Defined the NPY/NPY1R axis as pro-metastatic in pancreatic cancer and identified NPY1R+ cells as a colorectal cancer cell of origin, casting NPY1R as a context-dependent oncogenic driver distinct from its tumor-suppressive role elsewhere.","evidence":"Autochthonous and intrasplenic pancreatic metastasis models with genetic KO and BIBO3304; CreERT2 lineage tracing of NPY1R+ LGR5+ colon stem cells with Wnt/Kras/Trp53 manipulation","pmids":["40073121","40897804"],"confidence":"High","gaps":["Signaling driving migration and stemness downstream of NPY1R not resolved","Basis for opposing oncogenic vs suppressive roles across tissues unexplained"]},{"year":2025,"claim":"Linked NPY1R to the μ-opioid system, showing NPY1R+ spinal neurons require MOR for morphine analgesia and that NPY synergizes with morphine via NPY1R.","evidence":"In situ hybridization, conditional Oprm1 KO in NPY1R+ neurons, chemogenetics, intrathecal NPY with antagonist, Npy1r-/- mice, and spinal slice electrophysiology","pmids":["41738433"],"confidence":"High","gaps":["Molecular cross-talk between NPY1R and MOR signaling not defined","Convergent intracellular pathway not identified"]},{"year":2025,"claim":"Extended NPY1R signaling to additional peripheral effector pathways (CREB/NLRP3-driven senescence, vascular phenotypic switching via tyrosine phosphorylation, osteogenic PI3K/AKT/mTOR), broadening its mechanistic repertoire beyond cAMP inhibition.","evidence":"In vivo agonist/antagonist in ovarian granulosa cells; Co-IP of TK-NPY1R with TKI rescue in aneurysm model; iPSC osteogenesis with PAM inhibition","pmids":["42262763","39353356","41268237"],"confidence":"Medium","gaps":["Identity of the tyrosine kinase phosphorylating NPY1R not established","Osteogenic link to PI3K lacks direct binding/signaling evidence","Tissue-specific effector switching mechanism unknown"]},{"year":null,"claim":"How a single Gi-coupled, cAMP-inhibiting receptor produces tumor-suppressive effects in some cancers but pro-metastatic and stem-cell-origin effects in others, and how its signaling diverges across tissues, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying account of context-dependent NPY1R output","Receptor-proximal effector selection across tissues uncharacterized","Structural basis of ligand/effector coupling not addressed in corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[9,12,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,12,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,6,13]}],"complexes":[],"partners":["GALR2","TRKB","OPRM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P25929","full_name":"Neuropeptide Y receptor type 1","aliases":[],"length_aa":384,"mass_kda":44.4,"function":"Receptor for neuropeptide Y and peptide YY. The rank order of affinity of this receptor for pancreatic polypeptides is NPY > [Pro-34] PYY, PYY and [Leu-31, Pro-34] NPY > NPY (2-36) > [Ile-31, Gln-34] PP and PYY (3-36) > PP > NPY free acid","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P25929/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPY1R","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NPY1R","total_profiled":1310},"omim":[{"mim_id":"609985","title":"PANIC DISORDER 3; PAND3","url":"https://www.omim.org/entry/609985"},{"mim_id":"607122","title":"PROKINETICIN RECEPTOR 1; PROKR1","url":"https://www.omim.org/entry/607122"},{"mim_id":"605569","title":"G PROTEIN-COUPLED RECEPTOR 83; GPR83","url":"https://www.omim.org/entry/605569"},{"mim_id":"601790","title":"PANCREATIC POLYPEPTIDE RECEPTOR 1; PPYR1","url":"https://www.omim.org/entry/601790"},{"mim_id":"601770","title":"NEUROPEPTIDE Y RECEPTOR Y6; NPY6R","url":"https://www.omim.org/entry/601770"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":112.7}],"url":"https://www.proteinatlas.org/search/NPY1R"},"hgnc":{"alias_symbol":[],"prev_symbol":["NPYR"]},"alphafold":{"accession":"P25929","domains":[{"cath_id":"1.20.1070.10","chopping":"44-333","consensus_level":"high","plddt":91.038,"start":44,"end":333}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25929","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25929-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25929-F1-predicted_aligned_error_v6.png","plddt_mean":79.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPY1R","jax_strain_url":"https://www.jax.org/strain/search?query=NPY1R"},"sequence":{"accession":"P25929","fasta_url":"https://rest.uniprot.org/uniprotkb/P25929.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25929/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25929"}},"corpus_meta":[{"pmid":"15090072","id":"PMC_15090072","title":"A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R.","date":"2004","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15090072","citation_count":64,"is_preprint":false},{"pmid":"14525913","id":"PMC_14525913","title":"Chronic neuropeptide Y infusion into the lateral ventricle induces sustained feeding and obesity in mice lacking either Npy1r or Npy5r expression.","date":"2003","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/14525913","citation_count":38,"is_preprint":false},{"pmid":"32193153","id":"PMC_32193153","title":"MCM3AP-AS1 KD Inhibits Proliferation, Invasion, and Migration of PCa Cells via DNMT1/DNMT3 (A/B) Methylation-Mediated Upregulation of NPY1R.","date":"2020","source":"Molecular therapy. 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present.\",\n      \"method\": \"Chronic ICV NPY infusion in Npy1r and Npy5r knockout mice; measurement of food intake, fat pad weight, plasma insulin/leptin/corticosterone, and hypothalamic NPY/POMC mRNA\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with multiple orthogonal physiological and molecular readouts, replicated across two receptor KO lines\",\n      \"pmids\": [\"14525913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Conditional inactivation of Npy1r in Y5R-containing neurons (Npy1rY5R-/- mice) impairs behavioral flexibility (reversal learning) and causes decreased serotonergic fiber density and increased baseline neural activity (c-Fos) in the orbitofrontal cortex; acute escitalopram treatment restores OFC activity and behavioral flexibility, placing Y1R upstream of serotonergic tone in OFC circuits.\",\n      \"method\": \"Conditional KO mouse model (Npy1rY5R-/- mice); Morris water maze and water T-maze reversal learning; immunohistochemical quantification of c-Fos and 5-HT fibers in OFC; pharmacological rescue with SSRI escitalopram\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with multiple orthogonal behavioral and immunohistochemical readouts and pharmacological rescue in a single lab\",\n      \"pmids\": [\"29353053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NPY1R signaling in the medial prefrontal cortex enhances GABAergic inhibitory currents: maternally deprived mice show upregulated Npy1r expression and increased inhibitory synaptic inputs to mPFC neurons, and pharmacological blockade of NPY1R reduces GABAergic currents specifically in these animals.\",\n      \"method\": \"Maternal separation protocol in mice; RNAseq for gene expression changes; electrophysiological recordings (mPFC) with NPY1R pharmacological blockade; dendritic morphology analysis\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiological recordings with receptor blockade plus RNAseq and morphological analysis in a single lab, multiple orthogonal methods\",\n      \"pmids\": [\"32492699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional inactivation of Npy1r in limbic excitatory neurons produces sex-specific metabolic and behavioral phenotypes: male Npy1rrfb mice show HPA hyperactivation, anxiety, reduced body weight and adiposity; female Npy1rrfb mice show anxiety but no HPA or body weight changes, instead accumulating more WAT with compensatory reduction of AgRP in the arcuate nucleus, indicating estrogen-dependent relay that maintains homeostasis.\",\n      \"method\": \"Conditional KO mice (Npy1rrfb); behavioral tests; HPA axis hormone measurements; fat pad weighing; plasma leptin; AgRP immunoreactivity in arcuate nucleus; Npy1r mRNA quantification by brain region and sex\",\n      \"journal\": \"Hormones and behavior\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional KO with multiple physiological and neuroendocrine readouts across both sexes in a single lab\",\n      \"pmids\": [\"32755609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The lncRNA MCM3AP-AS1 recruits DNMT1/DNMT3A/DNMT3B to the NPY1R promoter, promoting its methylation and transcriptional silencing, thereby activating the MAPK pathway to drive prostate cancer cell proliferation, invasion, and migration; NPY1R overexpression reverses MCM3AP-AS1-driven tumor growth in vivo.\",\n      \"method\": \"RNA immunoprecipitation, RNA pull-down, chromatin immunoprecipitation (ChIP), methylation-specific PCR; NPY1R overexpression rescue; xenograft tumor model; scratch/Transwell/EdU/flow cytometry assays\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RIP, pulldown, ChIP, MSP, in vivo rescue) in a single lab; mechanistic link between lncRNA-DNMT recruitment and NPY1R promoter methylation is well-supported\",\n      \"pmids\": [\"32193153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NPY1R mediates inhibitory effects of NPY on estradiol-stimulated growth of ER+ breast cancer cells: NPY treatment reduces estradiol-stimulated cell growth, and this effect is reversed by the NPY1R antagonist BIBP-3226.\",\n      \"method\": \"NPY treatment with/without NPY1R antagonist BIBP-3226 in ER+ BC cell lines; cell growth assays; xenograft models; endocrine therapy resistance cell models in vitro and in vivo\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological antagonist rescue in multiple cell and xenograft models, single lab, two orthogonal experimental systems\",\n      \"pmids\": [\"35121782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Within the spinal dorsal horn, NPY1R interneurons (Y1-INs) segregate into three largely non-overlapping subpopulations (Grp/Npy1r, Npff/Npy1r, Cck/Npy1r); specifically, Grp/Npy1r interneurons are necessary for NPY-mediated analgesia in neuropathic pain — intrathecal Y1 agonist reduces neuropathic hypersensitivity in mice lacking Npy1r in CCK- and NPFF-INs but not in GRP-INs.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH) to characterize Y1-IN subpopulations in mice, non-human primates, and humans; chemogenetic inhibition of Npff/Npy1r-INs; conditional deletion of Npy1r from CCK-INs and NPFF-INs; intrathecal Y1 agonist [Leu31,Pro34]-NPY; neuropathic pain behavioral assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic deletion with pharmacological rescue across multiple neuron-type-specific KO lines, cross-species FISH validation in primates and humans\",\n      \"pmids\": [\"37824208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NPY1R forms heteroreceptor complexes with GALR2 and with TrkB in the dentate gyrus of the hippocampus; co-activation of NPY1R and GALR2 increases co-localization signals and neuroblast proliferation, and co-administration of NPY1R agonist with ketamine increases NPY1R-TrkB complex formation and BDNF expression, associated with enhanced neurogenesis and memory consolidation.\",\n      \"method\": \"In situ proximity ligation assay (PLA) for receptor co-localization; intracerebroventricular or intranasal drug administration; PCNA and DCX immunohistochemistry for neurogenesis; object-in-place memory task\",\n      \"journal\": \"Frontiers in cellular neuroscience / Cells / Expert opinion on therapeutic targets\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — PLA co-localization consistent across multiple studies from the same group; interaction not yet confirmed by co-IP or reconstitution, but replicated with two different receptor pairs\",\n      \"pmids\": [\"38425430\", \"38667284\", \"38622072\", \"38572811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NPY1R-TrkB and NPY1R-GALR2 heteroreceptor complexes in the ventral hippocampus are disrupted by ICV siRNA knockdown of NPY1R; this disruption does not alter hippocampal neurogenesis (PCNA counts), BDNF expression, or depressive-like behavior (forced swim test), indicating compensatory mechanisms that preserve plasticity despite receptor complex loss.\",\n      \"method\": \"ICV Accell siRNA knockdown of NPY1R; in situ PLA for NPY1R-GALR2 and NPY1R-TrkB complexes; PCNA immunolabeling; BDNF immunostaining; forced swim test\",\n      \"journal\": \"Journal of psychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with PLA validation of complex disruption and multiple functional readouts; single lab, confirms negative result for neurogenesis/behavior\",\n      \"pmids\": [\"41307298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPY1R exerts a cell-autonomous brake on adipocyte lipolysis: NPY dose-dependently attenuates lipolysis and cAMP signaling in primary human subcutaneous adipocytes; NPY1R expression correlates positively with adiposity and decreases after weight loss, with reduced NPY1R associated with enhanced beta-adrenergic-induced lipolysis.\",\n      \"method\": \"Single nuclei RNA sequencing of scWAT before/after lifestyle intervention; pharmacological NPY treatment in primary human adipocytes; cAMP signaling assays; meta-analysis of 23 clinical studies\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro functional assay in primary human adipocytes with cAMP readout, supported by snRNAseq and replicated across 23-study meta-analysis\",\n      \"pmids\": [\"41412283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPY/NPY1R signaling promotes pancreatic cancer metastasis to the liver: pancreas-specific and whole-body Npy1r knockout, as well as pharmacological inhibition with BIBO3304, significantly reduces liver metastasis in autochthonous KPR172HC mouse models and in an intrasplenic metastasis model; BIBO3304 reduces cancer cell migration on cell-derived matrices.\",\n      \"method\": \"Genetically engineered autochthonous KPR172HC mouse model with pancreas-specific and whole-body Npy1r KO; intrasplenic metastasis model; NPY1R antagonist BIBO3304 treatment; cell migration assays on cell-derived matrices\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in autochthonous model plus pharmacological inhibition in independent intrasplenic model, replicated across multiple experimental approaches in one study\",\n      \"pmids\": [\"40073121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPY1R identifies a colon-specific LGR5+ stem cell population in the middle and distal colorectum; selective dysregulation of Wnt signaling in NPY1R+ stem cells using CreERT2 lines drives colon cancer initiation predominantly in the rectum, establishing NPY1R+ stem cells as a source of colorectal cancer.\",\n      \"method\": \"CreERT2 mouse lines targeting NPY1R+ cells; conditional Wnt signaling activation; combination with oncogenic Kras and Trp53 loss; histological and cancer progression analysis\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic lineage-specific targeting with CreERT2 in multiple genetic backgrounds, with tumor initiation and progression as functional readout\",\n      \"pmids\": [\"40897804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"UHRF1 binds the NPY1R promoter, promotes its methylation, and suppresses NPY1R transcription in intestinal epithelial cells; UHRF1 deficiency upregulates NPY1R, which attenuates cAMP/PKA/CREB signaling, enhances NF-κB activation and proinflammatory IL-6/NLRP3 expression, and compromises intestinal epithelial barrier integrity.\",\n      \"method\": \"UHRF1 KO mouse model (intestinal epithelial-specific); human cell models; ChIP for UHRF1 binding to NPY1R promoter; methylation analysis; cAMP/PKA/CREB and NF-κB signaling assays; ELISA for IL-6; barrier integrity assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validation of UHRF1-NPY1R promoter interaction, KO mouse model with multiple downstream pathway measurements in a single study\",\n      \"pmids\": [\"41657307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MOR (μ-opioid receptor, Oprm1) is co-expressed in ~21% of NPY1R+ interneurons in the spinal dorsal horn; MOR activation in NPY1R+ interneurons is required for morphine analgesia — conditional deletion of Oprm1 from NPY1R+ neurons impairs morphine analgesia. Intrathecal NPY synergistically enhances morphine analgesia via NPY1R, an effect abolished by NPY1R antagonism or Npy1r knockout. NPY1R+ neuron hyperexcitability induced by inflammation is suppressed by morphine.\",\n      \"method\": \"In situ hybridization; conditional Oprm1 KO in NPY1R+ neurons (AAV-Npy1r-Cre-EGFP); chemogenetic approaches; intrathecal NPY +/- NPY1R antagonist; Npy1r-/- mice; whole-cell electrophysiology of spinal cord slices; multiple pain models\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (conditional KO, chemogenetics, pharmacology, electrophysiology, ISH) across multiple pain models in a single comprehensive study\",\n      \"pmids\": [\"41738433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPY1R is phosphorylated by tyrosine kinase (TK), and TK inhibition (TKI) suppresses NPY1R-mediated promotion of vascular smooth muscle cell phenotypic transition (contractile-to-synthetic), inflammatory response, and M1 macrophage polarization in an intracranial aneurysm mouse model; macrophage ablation abolished NPY1R overexpression-mediated promotion of aneurysm formation.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP) validating TK-NPY1R interaction; NPY1R overexpression in IA mouse model; TKI treatment; flow cytometry for immune cell populations; ELISA for inflammatory factors; HE staining\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for TK-NPY1R interaction, in vivo KO and pharmacological rescue; single lab with multiple readouts but abstract provides limited mechanistic detail on the kinase identity\",\n      \"pmids\": [\"39353356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPY1R activates PI3K/AKT/mTOR (PAM) signaling to support osteogenic differentiation: NPY1R suppression reduced osteogenic capacity of iPSCs, and PAM pathway inhibition with LY294002 decreased osteogenic activity; NPY1R and PAM pathway activation were confirmed in vivo in a rat periodontitis model during bone repair.\",\n      \"method\": \"Transcriptomic profiling of iPSC osteogenic differentiation; NPY1R knockdown; LY294002 PAM pathway inhibition; in vivo rat periodontitis model with NPY1R and pathway marker analysis\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, transcriptomics plus pharmacological inhibition without direct mechanistic linking of NPY1R to PI3K activation (no binding or signaling reconstitution)\",\n      \"pmids\": [\"41268237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPY1R overexpression in ovarian granulosa cells activates p-CREB signaling, promotes IL-6 and NLRP3 expression, induces ROS accumulation, ferroptosis, and mitochondrial dysfunction, accelerating ovarian senescence; NPY1R antagonist BIBO 3304 reverses these phenotypes in vivo.\",\n      \"method\": \"In vivo NPY1R agonist ([Leu31,Pro34]-NPY) and antagonist (BIBO 3304) administration in mice; transcriptome sequencing of aged human granulosa cells; ROS and mitochondrial assays; estrous cycle monitoring; follicular development analysis; CREB, IL-6, NLRP3 measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological agonist/antagonist in vivo rescue with multiple mechanistic readouts (CREB, NLRP3, ROS, ferroptosis) plus human transcriptomics, single lab\",\n      \"pmids\": [\"42262763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nobiletin (NOB) directly binds NPY1R (confirmed by molecular docking) and reduces Npy1r overexpression in pancreatic β-cells; NOB mitigates NPY1R-mediated β-cell insulin secretion deficiency by activating the RORs/Bmal1-YAP clock-modulatory pathway, suppressing YAP and activating Bmal1, thereby restoring insulin secretion in T2DM mouse models.\",\n      \"method\": \"Molecular docking for NOB-NPY1R interaction; Bmal1::Luc bioluminescence rhythmicity in MIN6 cells; NPY1R antagonist (BMS 193885) and palmitic acid/NPY interventions; T2DM mouse models (HFD+STZ and acute NPY hyperglycemia); Npy1r expression analysis in β-cells\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — molecular docking plus cell-based functional assays and two in vivo models; single lab; direct binding not confirmed by biophysical assay beyond docking\",\n      \"pmids\": [\"40913544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the gut, PYY-expressing colonic L-cells release PYY which acts on NPY1R-expressing enterochromaffin (EC) cells to enhance serotonin release and gut pain sensitivity in a female-specific estrogen-responsive paracrine circuit.\",\n      \"method\": \"Preprint: identification of NPY1R expression on EC cells; estrogen receptor alpha signaling manipulation; PYY/NPY1R pharmacological dissection in colonic circuit; gut pain behavioral assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, paracrine mechanism inferred from pharmacological and receptor expression studies without direct reconstitution of NPY1R signaling in EC cells\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NPY1R is a GPCR that, upon activation by NPY or PYY, inhibits cAMP signaling in multiple cell types (adipocytes, β-cells, neurons) and mediates NPY's orexigenic, analgesic, anxiolytic, and metabolic effects; in the spinal dorsal horn, NPY1R+ interneurons (particularly the Grp/Npy1r subset) are necessary for NPY-mediated analgesia and interact with MOR signaling to modulate morphine efficacy; in the brain, NPY1R enhances GABAergic inhibitory tone, forms heteroreceptor complexes with GALR2 and TrkB in the hippocampus to support neuroplasticity, and its limbic expression regulates HPA axis activity, anxiety, and aggression in a sex-dependent manner; in peripheral tissues, NPY1R is regulated epigenetically by UHRF1-mediated promoter methylation and by lncRNA-DNMT recruitment, suppresses lipolysis in adipocytes via cAMP/PKA, drives vascular smooth muscle cell phenotypic switching when phosphorylated by tyrosine kinase, marks a distinct LGR5+ colorectal stem cell population that serves as a cancer origin, and its NPY/NPY1R axis promotes pancreatic cancer metastasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPY1R (Y1 receptor) is a neuropeptide Y/peptide YY receptor that acts as a cell-autonomous brake on cAMP signaling and, through this and downstream cascades, governs metabolism, nociception, neuroplasticity, and stress physiology [#9]. In adipocytes NPY signaling through NPY1R dose-dependently attenuates lipolysis and cAMP signaling, with receptor abundance tracking adiposity such that reduced NPY1R licenses beta-adrenergic lipolysis [#9]; an analogous cAMP/PKA/CREB-restraining role operates in intestinal epithelium, where NPY1R induction limits NF-\\u03baB-driven IL-6/NLRP3 inflammation and supports barrier integrity [#12]. In the spinal dorsal horn, NPY1R-expressing interneurons partition into Grp/Npy1r, Npff/Npy1r, and Cck/Npy1r subsets, with the Grp/Npy1r population specifically required for NPY-mediated analgesia in neuropathic pain [#6]; a subset of these neurons co-express the \\u03bc-opioid receptor, and NPY acting through NPY1R synergistically enhances morphine analgesia [#13]. In limbic and cortical circuits, NPY1R enhances GABAergic inhibitory tone in the medial prefrontal cortex [#2], positions upstream of serotonergic tone in the orbitofrontal cortex to support behavioral flexibility [#1], and regulates HPA axis activity, anxiety, and body weight in a sex-dependent manner [#3]; in the hippocampus it forms heteroreceptor complexes with GALR2 and TrkB linked to neuroblast proliferation and memory [#7]. NPY1R transcription is epigenetically silenced by promoter methylation driven by UHRF1 [#12] and by lncRNA MCM3AP-AS1-mediated DNMT recruitment [#4]. The NPY/NPY1R axis drives cancer phenotypes, promoting pancreatic cancer liver metastasis [#10] and marking an LGR5+ colorectal stem cell population that serves as a cancer cell of origin [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established whether NPY1R is singularly required for NPY's orexigenic effect, revealing functional redundancy with the Y5 receptor.\",\n      \"evidence\": \"Chronic ICV NPY infusion in Npy1r and Npy5r knockout mice with feeding, adiposity, and hypothalamic mRNA readouts\",\n      \"pmids\": [\"14525913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve receptor-specific contributions when both are functional\", \"No cell-type or circuit resolution of the redundancy\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed NPY1R upstream of serotonergic tone in cortical circuits controlling behavioral flexibility, linking the receptor to executive function rather than only feeding.\",\n      \"evidence\": \"Conditional Npy1r KO in Y5R neurons; reversal learning, OFC c-Fos and 5-HT fiber immunohistochemistry, SSRI rescue\",\n      \"pmids\": [\"29353053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting NPY1R signaling to serotonergic fiber density unknown\", \"Receptor-intrinsic signaling step not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined NPY1R's circuit-level action in limbic/cortical neurons, showing it enhances GABAergic inhibition and controls HPA/anxiety/metabolic outputs sex-dependently.\",\n      \"evidence\": \"Maternal separation and conditional KO mice; mPFC electrophysiology with receptor blockade, RNAseq, neuroendocrine and adiposity measurements\",\n      \"pmids\": [\"32492699\", \"32755609\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of estrogen-dependent sex divergence not resolved\", \"Direct receptor signaling to GABAergic transmission not reconstituted\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified epigenetic silencing of NPY1R by lncRNA-directed DNMT recruitment as a driver of prostate cancer, framing NPY1R as a methylation-controlled tumor suppressor in this context.\",\n      \"evidence\": \"RIP, RNA pull-down, ChIP, methylation-specific PCR, NPY1R overexpression rescue, and xenografts in prostate cancer cells\",\n      \"pmids\": [\"32193153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How NPY1R loss feeds MAPK activation mechanistically unclear\", \"Single tumor-type model\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed NPY1R mediates NPY's growth-inhibitory effect on estrogen-driven breast cancer, extending its tumor-modulating role to hormone-responsive cancers.\",\n      \"evidence\": \"NPY treatment with NPY1R antagonist BIBP-3226 in ER+ breast cancer cells and xenografts\",\n      \"pmids\": [\"35121782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling linking NPY1R to growth inhibition undefined\", \"Single antagonist used\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved NPY1R spinal interneurons into molecular subtypes and pinpointed the Grp/Npy1r population as necessary for NPY analgesia, giving cell-type precision to the receptor's antinociceptive role.\",\n      \"evidence\": \"Cross-species FISH, chemogenetic inhibition, subtype-specific conditional Npy1r deletion, intrathecal Y1 agonist in neuropathic pain models\",\n      \"pmids\": [\"37824208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Circuit output of Grp/Npy1r neurons not fully mapped\", \"Signaling within these interneurons not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated NPY1R participates in heteroreceptor complexes with GALR2 and TrkB supporting hippocampal neurogenesis and memory, but follow-up knockdown showed plasticity is preserved via compensation, qualifying the functional weight of these complexes.\",\n      \"evidence\": \"In situ proximity ligation assay, ICV/intranasal drug administration, neurogenesis markers and memory tasks; ICV siRNA knockdown with PLA and behavioral readouts\",\n      \"pmids\": [\"38425430\", \"38667284\", \"38622072\", \"38572811\", \"41307298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Complexes shown only by PLA, not co-IP or reconstitution\", \"Compensatory mechanisms preserving plasticity unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the cell-autonomous, cAMP-restraining mechanism of NPY1R in human adipocytes and intestinal epithelium, unifying its metabolic and anti-inflammatory actions through cAMP/PKA/CREB suppression.\",\n      \"evidence\": \"Primary human adipocyte lipolysis and cAMP assays with snRNAseq and clinical meta-analysis; intestinal epithelial UHRF1 KO mouse with cAMP/PKA/CREB and NF-\\u03baB signaling readouts\",\n      \"pmids\": [\"41412283\", \"41657307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling to specific Gi/o subtypes not detailed in corpus\", \"Tissue-specific effector divergence not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed UHRF1-mediated promoter methylation as a second epigenetic axis controlling NPY1R, controlling intestinal inflammation and barrier function.\",\n      \"evidence\": \"Intestinal epithelial-specific UHRF1 KO mouse, ChIP, methylation analysis, downstream signaling and barrier assays\",\n      \"pmids\": [\"41657307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimuli regulating UHRF1 recruitment to NPY1R unknown\", \"Relationship to the lncRNA-DNMT axis not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the NPY/NPY1R axis as pro-metastatic in pancreatic cancer and identified NPY1R+ cells as a colorectal cancer cell of origin, casting NPY1R as a context-dependent oncogenic driver distinct from its tumor-suppressive role elsewhere.\",\n      \"evidence\": \"Autochthonous and intrasplenic pancreatic metastasis models with genetic KO and BIBO3304; CreERT2 lineage tracing of NPY1R+ LGR5+ colon stem cells with Wnt/Kras/Trp53 manipulation\",\n      \"pmids\": [\"40073121\", \"40897804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling driving migration and stemness downstream of NPY1R not resolved\", \"Basis for opposing oncogenic vs suppressive roles across tissues unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked NPY1R to the \\u03bc-opioid system, showing NPY1R+ spinal neurons require MOR for morphine analgesia and that NPY synergizes with morphine via NPY1R.\",\n      \"evidence\": \"In situ hybridization, conditional Oprm1 KO in NPY1R+ neurons, chemogenetics, intrathecal NPY with antagonist, Npy1r-/- mice, and spinal slice electrophysiology\",\n      \"pmids\": [\"41738433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cross-talk between NPY1R and MOR signaling not defined\", \"Convergent intracellular pathway not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended NPY1R signaling to additional peripheral effector pathways (CREB/NLRP3-driven senescence, vascular phenotypic switching via tyrosine phosphorylation, osteogenic PI3K/AKT/mTOR), broadening its mechanistic repertoire beyond cAMP inhibition.\",\n      \"evidence\": \"In vivo agonist/antagonist in ovarian granulosa cells; Co-IP of TK-NPY1R with TKI rescue in aneurysm model; iPSC osteogenesis with PAM inhibition\",\n      \"pmids\": [\"42262763\", \"39353356\", \"41268237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the tyrosine kinase phosphorylating NPY1R not established\", \"Osteogenic link to PI3K lacks direct binding/signaling evidence\", \"Tissue-specific effector switching mechanism unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single Gi-coupled, cAMP-inhibiting receptor produces tumor-suppressive effects in some cancers but pro-metastatic and stem-cell-origin effects in others, and how its signaling diverges across tissues, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying account of context-dependent NPY1R output\", \"Receptor-proximal effector selection across tissues uncharacterized\", \"Structural basis of ligand/effector coupling not addressed in corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [9, 12, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 12, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 6, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"GALR2\", \"TrkB\", \"OPRM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}