{"gene":"PANX3","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2018,"finding":"PANX3 channels exhibit similar dye uptake and ATP release properties to PANX1, demonstrated by in vitro channel assays comparing the two pannexins directly, suggesting functional equivalence as membrane channels.","method":"In vitro dye uptake assay and ATP release assay comparing Panx1 and Panx3 channels","journal":"Frontiers in molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct in vitro functional channel assay but single lab, single study, limited methodological detail in abstract","pmids":["29780304"],"is_preprint":false},{"year":2019,"finding":"Osteoblast-specific deletion of Panx3 (via Runx2-Cre) produced no detectable skeletal phenotype in postnatal bone remodeling, establishing that Panx3 expression in osteoblasts is dispensable for postnatal bone homeostasis. Ubiquitous Panx3 deletion caused a delay in endochondral ossification in neonates but not after weaning, accompanied by compensatory upregulation of Panx1, and newborn Panx3-deficient mice displayed significantly reduced serum glucose levels.","method":"Conditional knockout (Runx2-Cre × Panx3-fl/fl), global knockout, undecalcified histology with bone histomorphometry, serum glucose measurement, gene expression analysis","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean conditional and global KO models with bone histomorphometry and multiple phenotypic readouts, single lab but multiple orthogonal methods","pmids":["31202927"],"is_preprint":false},{"year":2021,"finding":"Loss of Panx3 in knockout mice reduced gene expression of Acan, Col1a1, Mmp13, and Runx2 in the aged intervertebral disc, altered COLX localization, and suppressed formation of hypertrophic cells in the annulus fibrosus following IVD injury, indicating that Panx3 mediates adaptive cellular hypertrophic responses to mechanical stress in the disc.","method":"Panx3 global knockout mice, histological analysis, gene expression analysis, immunolocalization","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined cellular phenotype and gene expression readouts, single lab, multiple orthogonal methods","pmids":["33499145"],"is_preprint":false},{"year":2020,"finding":"PANX3 was identified as a direct target of miR-431-5p by luciferase reporter assay; overexpression of PANX3 reversed the anti-tumor effects of miR-431-5p (apoptosis induction, proliferation/migration/invasion inhibition) in osteosarcoma cells, placing PANX3 downstream of miR-431-5p in osteosarcoma tumorigenesis.","method":"Luciferase reporter (DLR) assay, PANX3 overexpression rescue experiments, MTT assay, FITC/PI apoptosis assay, Transwell migration/invasion assay, Western blot, xenograft tumor model","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miRNA-target interaction with DLR assay and functional rescue experiments across multiple readouts, single lab","pmids":["32982413"],"is_preprint":false},{"year":2023,"finding":"Global Panx3-knockout mice show reduced E-cadherin stabilization, diminished Wnt signaling, impaired keratinocyte cell-cell and cell-matrix adhesion, reduced epidermal barrier function, and increased inflammatory signaling in the epidermis, establishing PANX3 as required for skin architecture, adhesion, barrier integrity, and inflammatory homeostasis.","method":"Global Panx3-KO mice, transcriptomic analysis of epidermis, primary keratinocyte culture adhesion assay, epidermal barrier function assay, histology","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO with multiple orthogonal readouts (transcriptomics, barrier function, adhesion assay, histology), single lab","pmids":["36813158"],"is_preprint":false},{"year":2025,"finding":"Overexpression of Panx3 in oral squamous cell carcinoma cells promotes ferroptosis and inhibits proliferation, migration, and invasion by suppressing AKT/mTOR signaling, as shown by decreased P-AKT, P-mTOR, GPX4, and SLC7A11 and increased ACSL4; the ferroptosis effect was rescued by the AKT activator SC79, and xenograft assays confirmed tumor suppression.","method":"PANX3 overexpression in SCC15 and CAL27 cells, Western blot, AKT activator (SC79) rescue, xenograft tumor assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway placement via pharmacological rescue, in vivo xenograft, multiple molecular readouts; single lab","pmids":["40441467"],"is_preprint":false},{"year":2026,"finding":"Panx3 expression is upregulated in the fracture callus during healing; Panx3-deficient mice show severely impaired bone regeneration, dysregulated inflammatory response, decreased type-H vessel formation, and differential expression of glucose metabolism genes including C1qtnf3 (a glucose-lowering adipokine). Neonatal Panx3-deficient mice exhibit three-fold elevated serum C1QTNF3 and hypoglycemia, linking Panx3 to energy metabolism regulation during bone repair.","method":"Panx3 global knockout mice, femoral osteotomy model, µCT, non-decalcified histology, gene expression analysis, genome-wide transcriptomics, serum glucose and C1QTNF3 measurements","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple orthogonal methods (µCT, histology, transcriptomics, serum assays), translational validation in human patient samples; single lab","pmids":["41857514"],"is_preprint":false},{"year":2018,"finding":"PANX3 was validated as a direct target gene of miR-367 by luciferase reporter assay; downregulation of miR-367 increased PANX3, β-catenin, and Wnt5b expression and promoted osteoblast proliferation and migration, placing PANX3 upstream of the Wnt/β-catenin pathway in fracture healing. NOTE: This paper has been retracted.","method":"Luciferase reporter assay, miR-367 mimic/inhibitor and siPANX3 transfection, Western blot, cell proliferation/apoptosis/migration assays — RETRACTED PAPER","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — paper is retracted; single lab, findings should not be relied upon","pmids":["30556206"],"is_preprint":false}],"current_model":"PANX3 is a channel-forming glycoprotein that releases ATP, regulates keratinocyte adhesion (via E-cadherin/Wnt signaling), epidermal barrier function, and inflammatory homeostasis in skin; mediates hypertrophic and adaptive cellular responses to mechanical stress in cartilaginous tissues; is required for bone fracture healing by coordinating the inflammatory response, type-H vessel formation, and glucose/energy metabolism (partly through C1QTNF3); suppresses oral squamous cell carcinoma progression by promoting ferroptosis via inhibition of the AKT/mTOR/GPX4/SLC7A11 axis; and can functionally compensate for PANX1 loss in sensory epithelia due to shared ATP-release and dye-uptake channel properties."},"narrative":{"mechanistic_narrative":"PANX3 is a channel-forming pannexin that releases ATP and supports dye uptake with functional properties closely matching PANX1, enabling it to compensate for PANX1 loss in shared channel contexts [PMID:29780304]. In skeletal and connective tissues PANX3 governs cellular responses to developmental and mechanical cues: its global loss delays neonatal endochondral ossification with compensatory Panx1 upregulation [PMID:31202927], and it drives adaptive hypertrophic responses in the intervertebral disc to mechanical stress, controlling expression of Acan, Col1a1, Mmp13, and Runx2 [PMID:33499145]. PANX3 is required for bone fracture healing, where it is upregulated in the callus and coordinates the inflammatory response, type-H vessel formation, and glucose/energy metabolism, the last linked to the glucose-lowering adipokine C1QTNF3 [PMID:41857514]; consistent with this metabolic role, neonatal Panx3-deficient mice show elevated serum C1QTNF3 and hypoglycemia [PMID:31202927, PMID:41857514]. In skin, PANX3 maintains epidermal architecture by stabilizing E-cadherin and sustaining Wnt signaling, supporting keratinocyte adhesion, barrier integrity, and inflammatory homeostasis [PMID:36813158]. In oral squamous cell carcinoma, PANX3 acts as a tumor suppressor by promoting ferroptosis through inhibition of AKT/mTOR signaling and downregulation of GPX4 and SLC7A11 [PMID:40441467].","teleology":[{"year":2018,"claim":"Established whether PANX3 functions as a bona fide membrane channel comparable to PANX1, addressing whether the two pannexins are functionally interchangeable.","evidence":"In vitro dye uptake and ATP release assays comparing Panx1 and Panx3 channels","pmids":["29780304"],"confidence":"Medium","gaps":["Single lab, limited methodological detail","No structural basis for channel gating defined","Compensation between PANX1 and PANX3 demonstrated in vitro but not in a defined physiological tissue here"]},{"year":2019,"claim":"Defined the tissue context of PANX3 requirement in bone, showing osteoblast expression is dispensable but global loss perturbs neonatal ossification and serum glucose.","evidence":"Runx2-Cre conditional and global Panx3 knockout mice with bone histomorphometry, gene expression, and serum glucose measurement","pmids":["31202927"],"confidence":"High","gaps":["Cell type responsible for the ossification delay not pinpointed","Mechanism linking Panx3 loss to reduced serum glucose unresolved","Compensatory Panx1 upregulation not mechanistically explained"]},{"year":2021,"claim":"Showed PANX3 mediates adaptive hypertrophic cellular responses to mechanical stress in the intervertebral disc, extending its role to mechanotransduction in cartilaginous tissue.","evidence":"Panx3 global knockout mice with IVD injury, histology, immunolocalization, and gene expression of Acan/Col1a1/Mmp13/Runx2","pmids":["33499145"],"confidence":"Medium","gaps":["Channel activity not directly tied to the hypertrophic response","Signaling pathway downstream of mechanical stress undefined","Single lab"]},{"year":2023,"claim":"Established PANX3 as required for skin architecture, linking it to E-cadherin stabilization, Wnt signaling, keratinocyte adhesion, barrier function, and inflammatory homeostasis.","evidence":"Global Panx3-KO mice with epidermal transcriptomics, keratinocyte adhesion assays, barrier function assays, and histology","pmids":["36813158"],"confidence":"High","gaps":["Direct molecular link between PANX3 channel activity and E-cadherin stabilization not established","Whether the inflammatory phenotype is cell-autonomous unknown"]},{"year":2025,"claim":"Placed PANX3 as a tumor suppressor in oral squamous cell carcinoma acting through AKT/mTOR-dependent ferroptosis.","evidence":"PANX3 overexpression in SCC15/CAL27 cells, Western blot of AKT/mTOR/GPX4/SLC7A11/ACSL4, SC79 pharmacological rescue, and xenograft assay","pmids":["40441467"],"confidence":"Medium","gaps":["Mechanism by which PANX3 suppresses AKT phosphorylation not defined","Based on overexpression rather than loss-of-function in tumor cells","Single lab"]},{"year":2026,"claim":"Integrated PANX3 into fracture healing as a coordinator of inflammation, type-H vessel formation, and glucose/energy metabolism via C1QTNF3.","evidence":"Panx3 global knockout mice with femoral osteotomy, µCT, histology, genome-wide transcriptomics, and serum glucose/C1QTNF3 measurements with human sample validation","pmids":["41857514"],"confidence":"High","gaps":["Direct causal role of C1QTNF3 in the healing defect not isolated","Whether vessel and metabolic phenotypes are interdependent unresolved","Cell-autonomous source of Panx3 in the callus undefined"]},{"year":null,"claim":"It remains unresolved how PANX3 channel activity (ATP release / dye uptake) mechanistically couples to its diverse tissue-level roles in adhesion, mechanotransduction, ferroptosis, and metabolism.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study directly links a defined channel conductance to a downstream signaling output","Direct physical partners of PANX3 not characterized in the corpus","No structural model of PANX3 in the available evidence"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96QZ0","full_name":"Pannexin-3","aliases":[],"length_aa":392,"mass_kda":44.7,"function":"Regulator of osteoblast differentiation by functioning as a Ca(2+) channel in the endoplasmic reticulum which regulates calmodulin (CaM) pathways. Allows ATP release into the extracellular space and activation or purinergic receptors","subcellular_location":"Cell membrane; Cell junction, gap junction; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96QZ0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PANX3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PANX3","total_profiled":1310},"omim":[{"mim_id":"613561","title":"MYOPATHY, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA 2; MLASA2","url":"https://www.omim.org/entry/613561"},{"mim_id":"610957","title":"TYROSYL-tRNA SYNTHETASE 2; YARS2","url":"https://www.omim.org/entry/610957"},{"mim_id":"608422","title":"PANNEXIN 3; PANX3","url":"https://www.omim.org/entry/608422"},{"mim_id":"608420","title":"PANNEXIN 1; PANX1","url":"https://www.omim.org/entry/608420"},{"mim_id":"600846","title":"PURINERGIC RECEPTOR P2X, LIGAND-GATED ION CHANNEL, 4; P2RX4","url":"https://www.omim.org/entry/600846"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PANX3"},"hgnc":{"alias_symbol":["Px3"],"prev_symbol":[]},"alphafold":{"accession":"Q96QZ0","domains":[{"cath_id":"-","chopping":"4-54_107-236_276-377","consensus_level":"high","plddt":83.3785,"start":4,"end":377}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QZ0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QZ0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QZ0-F1-predicted_aligned_error_v6.png","plddt_mean":81.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PANX3","jax_strain_url":"https://www.jax.org/strain/search?query=PANX3"},"sequence":{"accession":"Q96QZ0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QZ0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QZ0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QZ0"}},"corpus_meta":[{"pmid":"29780304","id":"PMC_29780304","title":"A Potential Compensatory Role of Panx3 in the VNO of a Panx1 Knock Out Mouse Model.","date":"2018","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29780304","citation_count":19,"is_preprint":false},{"pmid":"33499145","id":"PMC_33499145","title":"The Role of Panx3 in Age-Associated and Injury-Induced Intervertebral Disc Degeneration.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33499145","citation_count":18,"is_preprint":false},{"pmid":"27506198","id":"PMC_27506198","title":"Panx3 links body mass index and tumorigenesis in a genetically heterogeneous mouse model of carcinogen-induced cancer.","date":"2016","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27506198","citation_count":17,"is_preprint":false},{"pmid":"24267560","id":"PMC_24267560","title":"A new bi-modular endo-β-1,4-xylanase KRICT PX-3 from whole genome sequence of Paenibacillus terrae HPL-003.","date":"2013","source":"Enzyme and microbial technology","url":"https://pubmed.ncbi.nlm.nih.gov/24267560","citation_count":16,"is_preprint":false},{"pmid":"32982413","id":"PMC_32982413","title":"MicroRNA-431-5p Inhibits the Tumorigenesis of Osteosarcoma Through Targeting PANX3.","date":"2020","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/32982413","citation_count":13,"is_preprint":false},{"pmid":"16458963","id":"PMC_16458963","title":"Effective plasmid pX3 transduction in Lactobacillus delbrueckii by bacteriophage LL-H.","date":"2006","source":"Plasmid","url":"https://pubmed.ncbi.nlm.nih.gov/16458963","citation_count":12,"is_preprint":false},{"pmid":"27391460","id":"PMC_27391460","title":"High Relative Expression of Pannexin 3 (PANX3) in an Axillary Sweat Gland Carcinoma With Osteosarcomatous Transformation.","date":"2016","source":"The American Journal of dermatopathology","url":"https://pubmed.ncbi.nlm.nih.gov/27391460","citation_count":12,"is_preprint":false},{"pmid":"31202927","id":"PMC_31202927","title":"Osteoblast-specific expression of Panx3 is dispensable for postnatal bone remodeling.","date":"2019","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/31202927","citation_count":9,"is_preprint":false},{"pmid":"30556206","id":"PMC_30556206","title":"Retracted: Downregulation of microRNA-367 promotes osteoblasts growth and proliferation of mice during fracture by activating the PANX3-mediated Wnt/β-catenin pathway.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30556206","citation_count":9,"is_preprint":false},{"pmid":"27702477","id":"PMC_27702477","title":"Identification of a novel cellulose-binding domain within the endo-β-1,4-xylanase KRICT PX-3 from Paenibacillus terrae HPL-003.","date":"2016","source":"Enzyme and microbial technology","url":"https://pubmed.ncbi.nlm.nih.gov/27702477","citation_count":8,"is_preprint":false},{"pmid":"36448979","id":"PMC_36448979","title":"Noncoding rare variants in PANX3 are associated with chronic back pain.","date":"2022","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/36448979","citation_count":8,"is_preprint":false},{"pmid":"36813158","id":"PMC_36813158","title":"PANX3 Channels Regulate Architecture, Adhesion, Barrier Function, and Inflammation in the Skin.","date":"2023","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/36813158","citation_count":5,"is_preprint":false},{"pmid":"40441467","id":"PMC_40441467","title":"Panx3 mediates ferroptosis via the AKT/mTOR signaling pathway in oral squamous cell carcinoma.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/40441467","citation_count":2,"is_preprint":false},{"pmid":"39441379","id":"PMC_39441379","title":"Malignant epithelioid neoplasm with GLI1 gene rearrangement (PANX3::GLI1 transcript) and MDM2 gene amplification.","date":"2024","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39441379","citation_count":1,"is_preprint":false},{"pmid":"41857514","id":"PMC_41857514","title":"Panx3 deficiency in mice impairs bone fracture healing and causes transient hypoglycemia in neonatal animals.","date":"2026","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/41857514","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9460,"output_tokens":2229,"usd":0.030908,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9299,"output_tokens":2613,"usd":0.05591,"stage2_stop_reason":"end_turn"},"total_usd":0.086818,"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\": 2018,\n      \"finding\": \"PANX3 channels exhibit similar dye uptake and ATP release properties to PANX1, demonstrated by in vitro channel assays comparing the two pannexins directly, suggesting functional equivalence as membrane channels.\",\n      \"method\": \"In vitro dye uptake assay and ATP release assay comparing Panx1 and Panx3 channels\",\n      \"journal\": \"Frontiers in molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct in vitro functional channel assay but single lab, single study, limited methodological detail in abstract\",\n      \"pmids\": [\"29780304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Osteoblast-specific deletion of Panx3 (via Runx2-Cre) produced no detectable skeletal phenotype in postnatal bone remodeling, establishing that Panx3 expression in osteoblasts is dispensable for postnatal bone homeostasis. Ubiquitous Panx3 deletion caused a delay in endochondral ossification in neonates but not after weaning, accompanied by compensatory upregulation of Panx1, and newborn Panx3-deficient mice displayed significantly reduced serum glucose levels.\",\n      \"method\": \"Conditional knockout (Runx2-Cre × Panx3-fl/fl), global knockout, undecalcified histology with bone histomorphometry, serum glucose measurement, gene expression analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean conditional and global KO models with bone histomorphometry and multiple phenotypic readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31202927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of Panx3 in knockout mice reduced gene expression of Acan, Col1a1, Mmp13, and Runx2 in the aged intervertebral disc, altered COLX localization, and suppressed formation of hypertrophic cells in the annulus fibrosus following IVD injury, indicating that Panx3 mediates adaptive cellular hypertrophic responses to mechanical stress in the disc.\",\n      \"method\": \"Panx3 global knockout mice, histological analysis, gene expression analysis, immunolocalization\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined cellular phenotype and gene expression readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33499145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PANX3 was identified as a direct target of miR-431-5p by luciferase reporter assay; overexpression of PANX3 reversed the anti-tumor effects of miR-431-5p (apoptosis induction, proliferation/migration/invasion inhibition) in osteosarcoma cells, placing PANX3 downstream of miR-431-5p in osteosarcoma tumorigenesis.\",\n      \"method\": \"Luciferase reporter (DLR) assay, PANX3 overexpression rescue experiments, MTT assay, FITC/PI apoptosis assay, Transwell migration/invasion assay, Western blot, xenograft tumor model\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miRNA-target interaction with DLR assay and functional rescue experiments across multiple readouts, single lab\",\n      \"pmids\": [\"32982413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Global Panx3-knockout mice show reduced E-cadherin stabilization, diminished Wnt signaling, impaired keratinocyte cell-cell and cell-matrix adhesion, reduced epidermal barrier function, and increased inflammatory signaling in the epidermis, establishing PANX3 as required for skin architecture, adhesion, barrier integrity, and inflammatory homeostasis.\",\n      \"method\": \"Global Panx3-KO mice, transcriptomic analysis of epidermis, primary keratinocyte culture adhesion assay, epidermal barrier function assay, histology\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with multiple orthogonal readouts (transcriptomics, barrier function, adhesion assay, histology), single lab\",\n      \"pmids\": [\"36813158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Overexpression of Panx3 in oral squamous cell carcinoma cells promotes ferroptosis and inhibits proliferation, migration, and invasion by suppressing AKT/mTOR signaling, as shown by decreased P-AKT, P-mTOR, GPX4, and SLC7A11 and increased ACSL4; the ferroptosis effect was rescued by the AKT activator SC79, and xenograft assays confirmed tumor suppression.\",\n      \"method\": \"PANX3 overexpression in SCC15 and CAL27 cells, Western blot, AKT activator (SC79) rescue, xenograft tumor assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway placement via pharmacological rescue, in vivo xenograft, multiple molecular readouts; single lab\",\n      \"pmids\": [\"40441467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Panx3 expression is upregulated in the fracture callus during healing; Panx3-deficient mice show severely impaired bone regeneration, dysregulated inflammatory response, decreased type-H vessel formation, and differential expression of glucose metabolism genes including C1qtnf3 (a glucose-lowering adipokine). Neonatal Panx3-deficient mice exhibit three-fold elevated serum C1QTNF3 and hypoglycemia, linking Panx3 to energy metabolism regulation during bone repair.\",\n      \"method\": \"Panx3 global knockout mice, femoral osteotomy model, µCT, non-decalcified histology, gene expression analysis, genome-wide transcriptomics, serum glucose and C1QTNF3 measurements\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple orthogonal methods (µCT, histology, transcriptomics, serum assays), translational validation in human patient samples; single lab\",\n      \"pmids\": [\"41857514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PANX3 was validated as a direct target gene of miR-367 by luciferase reporter assay; downregulation of miR-367 increased PANX3, β-catenin, and Wnt5b expression and promoted osteoblast proliferation and migration, placing PANX3 upstream of the Wnt/β-catenin pathway in fracture healing. NOTE: This paper has been retracted.\",\n      \"method\": \"Luciferase reporter assay, miR-367 mimic/inhibitor and siPANX3 transfection, Western blot, cell proliferation/apoptosis/migration assays — RETRACTED PAPER\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — paper is retracted; single lab, findings should not be relied upon\",\n      \"pmids\": [\"30556206\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PANX3 is a channel-forming glycoprotein that releases ATP, regulates keratinocyte adhesion (via E-cadherin/Wnt signaling), epidermal barrier function, and inflammatory homeostasis in skin; mediates hypertrophic and adaptive cellular responses to mechanical stress in cartilaginous tissues; is required for bone fracture healing by coordinating the inflammatory response, type-H vessel formation, and glucose/energy metabolism (partly through C1QTNF3); suppresses oral squamous cell carcinoma progression by promoting ferroptosis via inhibition of the AKT/mTOR/GPX4/SLC7A11 axis; and can functionally compensate for PANX1 loss in sensory epithelia due to shared ATP-release and dye-uptake channel properties.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PANX3 is a channel-forming pannexin that releases ATP and supports dye uptake with functional properties closely matching PANX1, enabling it to compensate for PANX1 loss in shared channel contexts [#0]. In skeletal and connective tissues PANX3 governs cellular responses to developmental and mechanical cues: its global loss delays neonatal endochondral ossification with compensatory Panx1 upregulation [#1], and it drives adaptive hypertrophic responses in the intervertebral disc to mechanical stress, controlling expression of Acan, Col1a1, Mmp13, and Runx2 [#2]. PANX3 is required for bone fracture healing, where it is upregulated in the callus and coordinates the inflammatory response, type-H vessel formation, and glucose/energy metabolism, the last linked to the glucose-lowering adipokine C1QTNF3 [#6]; consistent with this metabolic role, neonatal Panx3-deficient mice show elevated serum C1QTNF3 and hypoglycemia [#1, #6]. In skin, PANX3 maintains epidermal architecture by stabilizing E-cadherin and sustaining Wnt signaling, supporting keratinocyte adhesion, barrier integrity, and inflammatory homeostasis [#4]. In oral squamous cell carcinoma, PANX3 acts as a tumor suppressor by promoting ferroptosis through inhibition of AKT/mTOR signaling and downregulation of GPX4 and SLC7A11 [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Established whether PANX3 functions as a bona fide membrane channel comparable to PANX1, addressing whether the two pannexins are functionally interchangeable.\",\n      \"evidence\": \"In vitro dye uptake and ATP release assays comparing Panx1 and Panx3 channels\",\n      \"pmids\": [\"29780304\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Single lab, limited methodological detail\", \"No structural basis for channel gating defined\", \"Compensation between PANX1 and PANX3 demonstrated in vitro but not in a defined physiological tissue here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the tissue context of PANX3 requirement in bone, showing osteoblast expression is dispensable but global loss perturbs neonatal ossification and serum glucose.\",\n      \"evidence\": \"Runx2-Cre conditional and global Panx3 knockout mice with bone histomorphometry, gene expression, and serum glucose measurement\",\n      \"pmids\": [\"31202927\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Cell type responsible for the ossification delay not pinpointed\", \"Mechanism linking Panx3 loss to reduced serum glucose unresolved\", \"Compensatory Panx1 upregulation not mechanistically explained\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed PANX3 mediates adaptive hypertrophic cellular responses to mechanical stress in the intervertebral disc, extending its role to mechanotransduction in cartilaginous tissue.\",\n      \"evidence\": \"Panx3 global knockout mice with IVD injury, histology, immunolocalization, and gene expression of Acan/Col1a1/Mmp13/Runx2\",\n      \"pmids\": [\"33499145\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Channel activity not directly tied to the hypertrophic response\", \"Signaling pathway downstream of mechanical stress undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established PANX3 as required for skin architecture, linking it to E-cadherin stabilization, Wnt signaling, keratinocyte adhesion, barrier function, and inflammatory homeostasis.\",\n      \"evidence\": \"Global Panx3-KO mice with epidermal transcriptomics, keratinocyte adhesion assays, barrier function assays, and histology\",\n      \"pmids\": [\"36813158\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular link between PANX3 channel activity and E-cadherin stabilization not established\", \"Whether the inflammatory phenotype is cell-autonomous unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed PANX3 as a tumor suppressor in oral squamous cell carcinoma acting through AKT/mTOR-dependent ferroptosis.\",\n      \"evidence\": \"PANX3 overexpression in SCC15/CAL27 cells, Western blot of AKT/mTOR/GPX4/SLC7A11/ACSL4, SC79 pharmacological rescue, and xenograft assay\",\n      \"pmids\": [\"40441467\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Mechanism by which PANX3 suppresses AKT phosphorylation not defined\", \"Based on overexpression rather than loss-of-function in tumor cells\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Integrated PANX3 into fracture healing as a coordinator of inflammation, type-H vessel formation, and glucose/energy metabolism via C1QTNF3.\",\n      \"evidence\": \"Panx3 global knockout mice with femoral osteotomy, µCT, histology, genome-wide transcriptomics, and serum glucose/C1QTNF3 measurements with human sample validation\",\n      \"pmids\": [\"41857514\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct causal role of C1QTNF3 in the healing defect not isolated\", \"Whether vessel and metabolic phenotypes are interdependent unresolved\", \"Cell-autonomous source of Panx3 in the callus undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how PANX3 channel activity (ATP release / dye uptake) mechanistically couples to its diverse tissue-level roles in adhesion, mechanotransduction, ferroptosis, and metabolism.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"No study directly links a defined channel conductance to a downstream signaling output\", \"Direct physical partners of PANX3 not characterized in the corpus\", \"No structural model of PANX3 in the available evidence\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}