{"gene":"OR4M1","run_date":"2026-04-29T11:37:57","timeline":{"discoveries":[{"year":2013,"finding":"Activation of OR4M1 in neuronal cultures attenuates abnormal tau phosphorylation, possibly through modulation of the JNK signaling pathway, as demonstrated using embryonic cortico-hippocampal neuronal cultures from NSE-OR4M1 transgenic mice.","method":"In vitro neuronal culture assay with OR4M1-transgenic mice; tau phosphorylation measured by site-specific antibodies (AT8, AT100, PHF-1 epitopes)","journal":"Journal of Alzheimer's disease : JAD","confidence":"Medium","confidence_rationale":"Tier 2 — functional assay with transgenic model and site-specific readout, single lab","pmids":["23241557"],"is_preprint":false},{"year":2016,"finding":"A 3-D structural model of OR4M1 was built and used for in silico ligand screening; in vitro activation of OR4M1 with compound ZINC10915775 selectively attenuated tau phosphorylation at Ser202/T205 (AT8) and Thr212/Ser214 (AT100), but not Ser396/404 (PHF-1), in NSE-OR4M1 transgenic neuronal cultures via JNK signaling modulation.","method":"In silico 3-D homology modeling; in vitro pharmacological activation of OR4M1 in transgenic neuronal cultures; phospho-tau immunoblotting","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 — computational model combined with in vitro functional assay and mutagenesis-level specificity readout; single lab","pmids":["26910498"],"is_preprint":false},{"year":2020,"finding":"Asprosin, the C-terminal cleavage product of profibrillin, exerts its glucogenic effect in the liver through OR4M1, an olfactory G-protein-coupled receptor, activating cAMP signaling.","method":"Genetic and pharmacological studies (receptor identification via genetic studies and downstream cAMP pathway activation)","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2–3 — receptor identification supported by genetic evidence and signaling pathway data; review but summarizing original experimental findings","pmids":["32198197"],"is_preprint":false},{"year":2022,"finding":"Asprosin promotes hepatic glucose release through activation of the cAMP signaling circuitry via its G protein-coupled receptor OR4M1, and also induces phosphorylation of ERK1/2 in ovarian cancer cells (SKOV-3) in vitro.","method":"Western blotting for ERK1/2 phosphorylation; cAMP signaling pathway analysis in OvCa cell lines","journal":"Journal of clinical medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct signaling readout (ERK1/2 phosphorylation) in cell line with asprosin treatment; single lab","pmids":["36233808"],"is_preprint":false},{"year":2025,"finding":"Citronellal blocks the asprosin binding site on OR4M1 (shown by molecular docking), and its administration reduces hepatic OR4M1 expression, lowers cAMP levels, attenuates protein kinase A activity, and reduces downstream gluconeogenic enzymes (glucose-6-phosphatase, PEPCK), establishing OR4M1 as a hepatic glucose regulator signaling through cAMP/PKA.","method":"Molecular docking; in vivo HFD/STZ rat model with pharmacological treatment; hepatic gene/protein expression analysis; cAMP and gluconeogenic enzyme assays","journal":"Molecular nutrition & food research","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo model with multiple downstream pathway readouts, supported by docking; single lab","pmids":["39821628"],"is_preprint":false},{"year":2025,"finding":"Hepatic knockdown of Olfr734 (the mouse ortholog of human OR4M1) in mice worsens hepatic glucose metabolism and increases hepatic lipid content in diet-induced obese mice, and OR4M1 expression is elevated in liver biopsies of male T2DM patients, establishing a direct functional role of this receptor in hepatic glucose and lipid homeostasis.","method":"Genetic knockdown (liver-specific Olfr734 inhibition) in mice; liver histology; glucose metabolism assays; human liver biopsy expression analysis","journal":"Nutrients","confidence":"High","confidence_rationale":"Tier 2 — clean liver-specific KO with defined metabolic phenotype, replicated in human biopsy samples","pmids":["40806011"],"is_preprint":false}],"current_model":"OR4M1 is an olfactory G protein-coupled receptor that functions as a hepatic receptor for asprosin, activating cAMP/PKA signaling to drive gluconeogenesis (via glucose-6-phosphatase and PEPCK); its liver-specific loss worsens glucose metabolism and promotes steatosis in mice, and its activation in neurons attenuates JNK-dependent tau hyperphosphorylation."},"narrative":{"teleology":[{"year":2013,"claim":"The first functional role for OR4M1 outside olfaction was established when its activation in neuronal cultures was shown to reduce pathological tau phosphorylation, linking an ectopic olfactory receptor to neurodegeneration-relevant signaling.","evidence":"Embryonic cortico-hippocampal cultures from NSE-OR4M1 transgenic mice; phospho-tau immunoblotting at AT8, AT100, PHF-1 epitopes","pmids":["23241557"],"confidence":"Medium","gaps":["Endogenous ligand for OR4M1 in neurons not identified","Mechanism connecting OR4M1 to JNK pathway not delineated","Single transgenic overexpression system, not confirmed with endogenous receptor"]},{"year":2016,"claim":"A synthetic agonist (ZINC10915775) identified via homology modeling selectively reduced tau phosphorylation at AT8 and AT100 but not PHF-1 epitopes, demonstrating epitope-specific signaling downstream of OR4M1 and implicating JNK as the mediating kinase.","evidence":"In silico 3-D homology model and virtual ligand screening; pharmacological activation in NSE-OR4M1 transgenic neuronal cultures with phospho-tau immunoblotting","pmids":["26910498"],"confidence":"Medium","gaps":["Binding affinity of ZINC10915775 for OR4M1 not measured directly","JNK involvement inferred from downstream readout, not from direct kinase inhibition epistasis","In vivo validation of agonist effects absent"]},{"year":2020,"claim":"Identification of asprosin as the endogenous ligand for OR4M1 resolved the receptor's physiological context, establishing it as the hepatic mediator of asprosin-driven cAMP signaling and gluconeogenesis.","evidence":"Genetic and pharmacological receptor identification studies with cAMP pathway activation readouts","pmids":["32198197"],"confidence":"Medium","gaps":["Direct binding assay data (e.g., radioligand or SPR) between asprosin and OR4M1 not provided in this report","Relative contribution of OR4M1 versus other potential asprosin receptors not quantified","Findings summarized in a review context rather than primary research article"]},{"year":2022,"claim":"Demonstration that asprosin-OR4M1 signaling activates ERK1/2 in ovarian cancer cells expanded the receptor's signaling repertoire beyond cAMP/PKA, suggesting tissue-dependent pathway engagement.","evidence":"Western blotting for ERK1/2 phosphorylation in SKOV-3 ovarian cancer cells treated with asprosin","pmids":["36233808"],"confidence":"Medium","gaps":["OR4M1 dependence of ERK1/2 activation not confirmed by receptor knockdown in these cells","Functional consequences of ERK1/2 activation for cancer cell behavior not characterized","Single cell line study"]},{"year":2025,"claim":"Pharmacological blockade of OR4M1 by citronellal in a diabetic rat model reduced cAMP, PKA activity, and gluconeogenic enzymes, providing in vivo evidence that the asprosin-OR4M1-cAMP/PKA-gluconeogenesis axis is druggable.","evidence":"Molecular docking of citronellal to OR4M1; HFD/STZ rat model with hepatic cAMP, PKA, G6Pase, and PEPCK measurements","pmids":["39821628"],"confidence":"Medium","gaps":["Citronellal specificity for OR4M1 versus other olfactory receptors not validated by genetic knockout control","Direct competitive binding data absent; reliance on molecular docking","Long-term metabolic outcomes of citronellal treatment not assessed"]},{"year":2025,"claim":"Liver-specific knockdown of Olfr734 (mouse OR4M1 ortholog) causally linked the receptor to hepatic glucose and lipid homeostasis, and elevated OR4M1 in human T2DM liver biopsies supported clinical relevance.","evidence":"Liver-specific genetic knockdown in diet-induced obese mice; glucose metabolism and lipid content assays; human liver biopsy expression analysis","pmids":["40806011"],"confidence":"High","gaps":["Whether OR4M1 upregulation in human T2DM is compensatory or pathogenic is unresolved","Lipid accumulation mechanism downstream of OR4M1 loss not defined","Female-specific data not reported for human liver expression"]},{"year":null,"claim":"The structural basis of asprosin-OR4M1 interaction, the mechanism by which OR4M1 loss drives steatosis, and whether neuronal OR4M1 signaling is physiologically relevant in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal or cryo-EM structure of OR4M1 with asprosin exists","Lipid accumulation downstream of OR4M1 deficiency has no defined molecular mechanism","In vivo neuronal function of OR4M1 and endogenous brain ligand unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,3,4,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,5]}],"complexes":[],"partners":["FBN1"],"other_free_text":[]},"mechanistic_narrative":"OR4M1 is an olfactory G protein-coupled receptor that functions as the hepatic receptor for asprosin, coupling ligand binding to cAMP/PKA signaling to promote gluconeogenesis through induction of glucose-6-phosphatase and PEPCK [PMID:32198197, PMID:39821628]. Liver-specific loss of its mouse ortholog Olfr734 worsens hepatic glucose metabolism and promotes steatosis in diet-induced obese mice, and OR4M1 expression is elevated in liver biopsies from male type 2 diabetes patients, establishing a direct role in hepatic glucose and lipid homeostasis [PMID:40806011]. Beyond the liver, activation of OR4M1 in neuronal cultures attenuates abnormal tau hyperphosphorylation at specific epitopes (AT8, AT100) through modulation of JNK signaling [PMID:23241557, PMID:26910498]. Asprosin-OR4M1 signaling also activates ERK1/2 phosphorylation in ovarian cancer cells, indicating pathway engagement outside hepatocytes [PMID:36233808]."},"prefetch_data":{"uniprot":{"accession":"Q8NGD0","full_name":"Olfactory receptor 4M1","aliases":["Olfactory receptor OR14-7"],"length_aa":313,"mass_kda":35.5,"function":"Olfactory receptor that acts as a receptor of Asprosin hormone, potentially at the surface of hepatocytes and may help to promote hepatocyte glucose release","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8NGD0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/OR4M1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1090,"dependency_fraction":0.001834862385321101},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/OR4M1","total_profiled":1310},"omim":[{"mim_id":"619939","title":"OLFACTORY RECEPTOR, FAMILY 4, SUBFAMILY M, MEMBER 1; OR4M1","url":"https://www.omim.org/entry/619939"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/OR4M1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8NGD0","domains":[{"cath_id":"1.20.1070.10","chopping":"10-307","consensus_level":"high","plddt":90.9745,"start":10,"end":307}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NGD0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NGD0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NGD0-F1-predicted_aligned_error_v6.png","plddt_mean":89.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=OR4M1","jax_strain_url":"https://www.jax.org/strain/search?query=OR4M1"},"sequence":{"accession":"Q8NGD0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NGD0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NGD0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NGD0"}},"corpus_meta":[{"pmid":"23241557","id":"PMC_23241557","title":"Decreased level of olfactory receptors in blood cells following traumatic brain injury and potential association with tauopathy.","date":"2013","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/23241557","citation_count":41,"is_preprint":false},{"pmid":"32198197","id":"PMC_32198197","title":"Energy Regulation Mechanism and Therapeutic Potential of Asprosin.","date":"2020","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/32198197","citation_count":33,"is_preprint":false},{"pmid":"33112803","id":"PMC_33112803","title":"Discovery of a possible role of asprosin in ovarian follicular function.","date":"2021","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/33112803","citation_count":27,"is_preprint":false},{"pmid":"34386072","id":"PMC_34386072","title":"A pancancer overview of FBN1, asprosin and its cognate receptor OR4M1 with detailed expression profiling in ovarian cancer.","date":"2021","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34386072","citation_count":26,"is_preprint":false},{"pmid":"34781067","id":"PMC_34781067","title":"A potential role of fibrillin-1 (FBN1) mRNA and asprosin in follicular development in water buffalo.","date":"2021","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/34781067","citation_count":18,"is_preprint":false},{"pmid":"35707591","id":"PMC_35707591","title":"Asprosin, a C-Terminal Cleavage Product of Fibrillin 1 Encoded by the FBN1 Gene, in Health and Disease.","date":"2022","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/35707591","citation_count":17,"is_preprint":false},{"pmid":"36233808","id":"PMC_36233808","title":"Differential Regulation of Genes by the Glucogenic Hormone Asprosin in Ovarian Cancer.","date":"2022","source":"Journal of clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36233808","citation_count":12,"is_preprint":false},{"pmid":"36978520","id":"PMC_36978520","title":"Comparative Analysis of Olfactory Receptor Repertoires Sheds Light on the Diet Adaptation of the Bamboo-Eating Giant Panda Based on the Chromosome-Level Genome.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/36978520","citation_count":6,"is_preprint":false},{"pmid":"37167929","id":"PMC_37167929","title":"Developmental and hormonal regulation of FBN1 and OR4M1 mRNA in bovine granulosa cells.","date":"2023","source":"Domestic animal endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37167929","citation_count":3,"is_preprint":false},{"pmid":"40871563","id":"PMC_40871563","title":"Effects of Asprosin and Role of TLR4 as a Biomarker in Endometrial Cancer.","date":"2025","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40871563","citation_count":1,"is_preprint":false},{"pmid":"40806011","id":"PMC_40806011","title":"Hepatic Olfr734 Deficiency Worsens Hepatic Glucose Metabolism and Induces MASLD in Mice.","date":"2025","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/40806011","citation_count":1,"is_preprint":false},{"pmid":"26910498","id":"PMC_26910498","title":"In Silico Modeling of Novel Drug Ligands for Treatment of Concussion Associated Tauopathy.","date":"2016","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26910498","citation_count":1,"is_preprint":false},{"pmid":"39821628","id":"PMC_39821628","title":"Citronellal Alleviates Insulin Resistance in High-Fat Diet/Streptozocin Model: Role of Asprosin/Olfactory Receptor Axis.","date":"2025","source":"Molecular nutrition & food research","url":"https://pubmed.ncbi.nlm.nih.gov/39821628","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8880,"output_tokens":1447,"usd":0.024172},"stage2":{"model":"claude-opus-4-6","input_tokens":4686,"output_tokens":1966,"usd":0.10887},"total_usd":0.133042,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Activation of OR4M1 in neuronal cultures attenuates abnormal tau phosphorylation, possibly through modulation of the JNK signaling pathway, as demonstrated using embryonic cortico-hippocampal neuronal cultures from NSE-OR4M1 transgenic mice.\",\n      \"method\": \"In vitro neuronal culture assay with OR4M1-transgenic mice; tau phosphorylation measured by site-specific antibodies (AT8, AT100, PHF-1 epitopes)\",\n      \"journal\": \"Journal of Alzheimer's disease : JAD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional assay with transgenic model and site-specific readout, single lab\",\n      \"pmids\": [\"23241557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A 3-D structural model of OR4M1 was built and used for in silico ligand screening; in vitro activation of OR4M1 with compound ZINC10915775 selectively attenuated tau phosphorylation at Ser202/T205 (AT8) and Thr212/Ser214 (AT100), but not Ser396/404 (PHF-1), in NSE-OR4M1 transgenic neuronal cultures via JNK signaling modulation.\",\n      \"method\": \"In silico 3-D homology modeling; in vitro pharmacological activation of OR4M1 in transgenic neuronal cultures; phospho-tau immunoblotting\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — computational model combined with in vitro functional assay and mutagenesis-level specificity readout; single lab\",\n      \"pmids\": [\"26910498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Asprosin, the C-terminal cleavage product of profibrillin, exerts its glucogenic effect in the liver through OR4M1, an olfactory G-protein-coupled receptor, activating cAMP signaling.\",\n      \"method\": \"Genetic and pharmacological studies (receptor identification via genetic studies and downstream cAMP pathway activation)\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — receptor identification supported by genetic evidence and signaling pathway data; review but summarizing original experimental findings\",\n      \"pmids\": [\"32198197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Asprosin promotes hepatic glucose release through activation of the cAMP signaling circuitry via its G protein-coupled receptor OR4M1, and also induces phosphorylation of ERK1/2 in ovarian cancer cells (SKOV-3) in vitro.\",\n      \"method\": \"Western blotting for ERK1/2 phosphorylation; cAMP signaling pathway analysis in OvCa cell lines\",\n      \"journal\": \"Journal of clinical medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct signaling readout (ERK1/2 phosphorylation) in cell line with asprosin treatment; single lab\",\n      \"pmids\": [\"36233808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Citronellal blocks the asprosin binding site on OR4M1 (shown by molecular docking), and its administration reduces hepatic OR4M1 expression, lowers cAMP levels, attenuates protein kinase A activity, and reduces downstream gluconeogenic enzymes (glucose-6-phosphatase, PEPCK), establishing OR4M1 as a hepatic glucose regulator signaling through cAMP/PKA.\",\n      \"method\": \"Molecular docking; in vivo HFD/STZ rat model with pharmacological treatment; hepatic gene/protein expression analysis; cAMP and gluconeogenic enzyme assays\",\n      \"journal\": \"Molecular nutrition & food research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo model with multiple downstream pathway readouts, supported by docking; single lab\",\n      \"pmids\": [\"39821628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hepatic knockdown of Olfr734 (the mouse ortholog of human OR4M1) in mice worsens hepatic glucose metabolism and increases hepatic lipid content in diet-induced obese mice, and OR4M1 expression is elevated in liver biopsies of male T2DM patients, establishing a direct functional role of this receptor in hepatic glucose and lipid homeostasis.\",\n      \"method\": \"Genetic knockdown (liver-specific Olfr734 inhibition) in mice; liver histology; glucose metabolism assays; human liver biopsy expression analysis\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean liver-specific KO with defined metabolic phenotype, replicated in human biopsy samples\",\n      \"pmids\": [\"40806011\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"OR4M1 is an olfactory G protein-coupled receptor that functions as a hepatic receptor for asprosin, activating cAMP/PKA signaling to drive gluconeogenesis (via glucose-6-phosphatase and PEPCK); its liver-specific loss worsens glucose metabolism and promotes steatosis in mice, and its activation in neurons attenuates JNK-dependent tau hyperphosphorylation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"OR4M1 is an olfactory G protein-coupled receptor that functions as the hepatic receptor for asprosin, coupling ligand binding to cAMP/PKA signaling to promote gluconeogenesis through induction of glucose-6-phosphatase and PEPCK [PMID:32198197, PMID:39821628]. Liver-specific loss of its mouse ortholog Olfr734 worsens hepatic glucose metabolism and promotes steatosis in diet-induced obese mice, and OR4M1 expression is elevated in liver biopsies from male type 2 diabetes patients, establishing a direct role in hepatic glucose and lipid homeostasis [PMID:40806011]. Beyond the liver, activation of OR4M1 in neuronal cultures attenuates abnormal tau hyperphosphorylation at specific epitopes (AT8, AT100) through modulation of JNK signaling [PMID:23241557, PMID:26910498]. Asprosin-OR4M1 signaling also activates ERK1/2 phosphorylation in ovarian cancer cells, indicating pathway engagement outside hepatocytes [PMID:36233808].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"The first functional role for OR4M1 outside olfaction was established when its activation in neuronal cultures was shown to reduce pathological tau phosphorylation, linking an ectopic olfactory receptor to neurodegeneration-relevant signaling.\",\n      \"evidence\": \"Embryonic cortico-hippocampal cultures from NSE-OR4M1 transgenic mice; phospho-tau immunoblotting at AT8, AT100, PHF-1 epitopes\",\n      \"pmids\": [\"23241557\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Endogenous ligand for OR4M1 in neurons not identified\",\n        \"Mechanism connecting OR4M1 to JNK pathway not delineated\",\n        \"Single transgenic overexpression system, not confirmed with endogenous receptor\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A synthetic agonist (ZINC10915775) identified via homology modeling selectively reduced tau phosphorylation at AT8 and AT100 but not PHF-1 epitopes, demonstrating epitope-specific signaling downstream of OR4M1 and implicating JNK as the mediating kinase.\",\n      \"evidence\": \"In silico 3-D homology model and virtual ligand screening; pharmacological activation in NSE-OR4M1 transgenic neuronal cultures with phospho-tau immunoblotting\",\n      \"pmids\": [\"26910498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding affinity of ZINC10915775 for OR4M1 not measured directly\",\n        \"JNK involvement inferred from downstream readout, not from direct kinase inhibition epistasis\",\n        \"In vivo validation of agonist effects absent\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of asprosin as the endogenous ligand for OR4M1 resolved the receptor's physiological context, establishing it as the hepatic mediator of asprosin-driven cAMP signaling and gluconeogenesis.\",\n      \"evidence\": \"Genetic and pharmacological receptor identification studies with cAMP pathway activation readouts\",\n      \"pmids\": [\"32198197\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding assay data (e.g., radioligand or SPR) between asprosin and OR4M1 not provided in this report\",\n        \"Relative contribution of OR4M1 versus other potential asprosin receptors not quantified\",\n        \"Findings summarized in a review context rather than primary research article\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that asprosin-OR4M1 signaling activates ERK1/2 in ovarian cancer cells expanded the receptor's signaling repertoire beyond cAMP/PKA, suggesting tissue-dependent pathway engagement.\",\n      \"evidence\": \"Western blotting for ERK1/2 phosphorylation in SKOV-3 ovarian cancer cells treated with asprosin\",\n      \"pmids\": [\"36233808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"OR4M1 dependence of ERK1/2 activation not confirmed by receptor knockdown in these cells\",\n        \"Functional consequences of ERK1/2 activation for cancer cell behavior not characterized\",\n        \"Single cell line study\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Pharmacological blockade of OR4M1 by citronellal in a diabetic rat model reduced cAMP, PKA activity, and gluconeogenic enzymes, providing in vivo evidence that the asprosin-OR4M1-cAMP/PKA-gluconeogenesis axis is druggable.\",\n      \"evidence\": \"Molecular docking of citronellal to OR4M1; HFD/STZ rat model with hepatic cAMP, PKA, G6Pase, and PEPCK measurements\",\n      \"pmids\": [\"39821628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Citronellal specificity for OR4M1 versus other olfactory receptors not validated by genetic knockout control\",\n        \"Direct competitive binding data absent; reliance on molecular docking\",\n        \"Long-term metabolic outcomes of citronellal treatment not assessed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Liver-specific knockdown of Olfr734 (mouse OR4M1 ortholog) causally linked the receptor to hepatic glucose and lipid homeostasis, and elevated OR4M1 in human T2DM liver biopsies supported clinical relevance.\",\n      \"evidence\": \"Liver-specific genetic knockdown in diet-induced obese mice; glucose metabolism and lipid content assays; human liver biopsy expression analysis\",\n      \"pmids\": [\"40806011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether OR4M1 upregulation in human T2DM is compensatory or pathogenic is unresolved\",\n        \"Lipid accumulation mechanism downstream of OR4M1 loss not defined\",\n        \"Female-specific data not reported for human liver expression\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of asprosin-OR4M1 interaction, the mechanism by which OR4M1 loss drives steatosis, and whether neuronal OR4M1 signaling is physiologically relevant in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No co-crystal or cryo-EM structure of OR4M1 with asprosin exists\",\n        \"Lipid accumulation downstream of OR4M1 deficiency has no defined molecular mechanism\",\n        \"In vivo neuronal function of OR4M1 and endogenous brain ligand unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 3, 4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FBN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}