{"gene":"CLDN7","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2021,"finding":"Intestinal epithelial Cldn-7 knockout (Cldn7fl/fl;villin-CreERT2 mice) disrupts tight junction integrity, increases intercellular permeability, and promotes susceptibility to experimental colitis and colitis-associated carcinogenesis, with activation of Wnt/β-catenin signaling in the tumor context.","method":"Inducible intestinal conditional knockout mouse model with AOM/DSS-induced colitis and CAC; FITC-dextran permeability assay; histology; immunostaining for β-catenin/TCF/LEF pathway components","journal":"Oncoimmunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined cellular and molecular phenotypes (barrier permeability, Wnt pathway activation), multiple readouts, in vivo model","pmids":["34026335"],"is_preprint":false},{"year":2024,"finding":"Cldn-7 deficiency in intestinal epithelial cells alters gut microbiota composition (diversity and abundance) and this dysbiosis mediates intestinal inflammation; antibiotic-induced microbiota depletion reduces colitis severity in Cldn-7 KO mice, and co-housing (microbiota transfer) partially restores inflammation, placing Cldn-7 upstream of microbiota-mediated inflammatory signaling.","method":"Inducible intestinal conditional Cldn-7 KO mice; antibiotic treatment; co-housing experiment; 16S rRNA amplicon sequencing; qRT-PCR for inflammatory factors and AMPs; AB-PAS/Muc2 staining for mucus layer","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with epistasis-style antibiotic/co-housing rescue experiments and microbiome sequencing, single lab","pmids":["39004000"],"is_preprint":false},{"year":2025,"finding":"ACSS2-mediated histone H4 lysine 12 crotonylation (H4K12cr) upregulates CLDN7 transcription to fortify the intestinal epithelial barrier; ACSS2 inhibition reduces H4K12cr at the CLDN7 locus, decreasing its expression and impairing barrier integrity, while crotonate supplementation augments this pathway.","method":"Genetic/pharmacological ACSS2 inhibition in mice; chromatin studies (H4K12cr at CLDN7 locus); crotonate supplementation rescue; intestinal barrier integrity assays; colitis model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established with genetic inhibition, histone modification measurement, and rescue by crotonate; single lab","pmids":["40650658"],"is_preprint":false},{"year":2018,"finding":"CLDN7 overexpression in gastric cancer cells promotes cell proliferation, invasion, and maintenance of the mesenchymal state (epithelial-mesenchymal transition), indicating an oncogenic function for CLDN7 in this context.","method":"CLDN7 gain- and loss-of-function in gastric cancer cell lines; proliferation, invasion, and EMT marker assays","journal":"Neoplasma","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional cell-line KD/OE with defined phenotypic readouts (proliferation, invasion, EMT markers), single lab","pmids":["29788731"],"is_preprint":false},{"year":2020,"finding":"CLDN7 is a direct transcriptional target of miR-1193 in cervical cancer cells; miR-1193 overexpression suppresses proliferation, invasion, and migration, and restoration of CLDN7 rescues these tumor-suppressing effects, confirming CLDN7 acts downstream of miR-1193.","method":"Luciferase reporter assay (3'UTR); qRT-PCR and Western blot; CCK-8, transwell, and wound-healing assays; CLDN7 rescue experiment in miR-1193-overexpressing cells","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms direct miRNA-target interaction; rescue experiment establishes epistasis; single lab with multiple orthogonal methods","pmids":["32547067"],"is_preprint":false},{"year":2026,"finding":"CLDN7 is preferentially localized to the cytoplasmic membrane of ovarian cancer cells; knockdown of CLDN7 in cisplatin-resistant SKOV3/DDP cells decreases autophagy and mitophagy (LC3, mitophagy markers), reduces migration and invasion, and enhances cisplatin sensitivity both in vitro and in xenograft models, indicating CLDN7 promotes cisplatin resistance through regulation of mitophagy.","method":"siRNA knockdown; Western blot for autophagy/mitophagy markers; immunofluorescence colocalization (LC3/MitoTracker); CCK-8 cisplatin sensitivity; transwell migration/invasion; xenograft tumor growth assay","journal":"Journal of ovarian research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with multiple orthogonal methods including in vivo xenograft; single lab","pmids":["42057112"],"is_preprint":false}],"current_model":"CLDN7 is a tight junction transmembrane protein that maintains intestinal epithelial barrier integrity and cell polarity; its loss disrupts paracellular permeability, dysregulates gut microbiota, and triggers inflammatory and Wnt/β-catenin-driven tumorigenic cascades, while its transcription is epigenetically regulated by ACSS2-mediated H4K12 crotonylation and post-transcriptionally by miR-1193; in cancer contexts CLDN7 can act oncogenically by promoting EMT, invasion, and cisplatin resistance via mitophagy regulation."},"narrative":{"mechanistic_narrative":"CLDN7 is a tight junction component that maintains intestinal epithelial barrier integrity, with its loss disrupting paracellular permeability and predisposing to inflammation and tumorigenesis [PMID:34026335]. Conditional intestinal knockout compromises tight junction integrity, raises intercellular permeability, and promotes susceptibility to experimental colitis and colitis-associated carcinogenesis with activation of Wnt/β-catenin signaling [PMID:34026335]; barrier loss also reshapes gut microbiota composition, and this dysbiosis is itself a driver of the resulting inflammation, as antibiotic depletion attenuates and microbiota transfer restores colitis severity in knockout mice [PMID:39004000]. CLDN7 transcription is reinforced epigenetically through ACSS2-mediated histone H4K12 crotonylation at the CLDN7 locus, a pathway augmented by crotonate that fortifies the barrier [PMID:40650658]. In cancer contexts CLDN7 instead behaves oncogenically: it is a direct target of the tumor-suppressive miR-1193 in cervical cancer [PMID:32547067], its overexpression drives proliferation, invasion, and epithelial-mesenchymal transition in gastric cancer [PMID:29788731], and in cisplatin-resistant ovarian cancer cells it promotes autophagy/mitophagy, migration, invasion, and chemoresistance [PMID:42057112].","teleology":[{"year":2021,"claim":"Established that intestinal CLDN7 is required for tight junction barrier integrity and that its loss links barrier failure to inflammation and Wnt-driven carcinogenesis.","evidence":"Inducible intestinal conditional knockout mice with AOM/DSS colitis/CAC, FITC-dextran permeability, and β-catenin/TCF/LEF immunostaining","pmids":["34026335"],"confidence":"High","gaps":["Does not resolve whether Wnt activation is a direct consequence of CLDN7 loss or secondary to barrier breach","No structural or claudin-channel mechanism for the permeability defect"]},{"year":2024,"claim":"Placed CLDN7 upstream of microbiota-mediated inflammation, showing that barrier loss-induced dysbiosis is causally required for the inflammatory phenotype.","evidence":"Conditional KO mice with antibiotic depletion, co-housing microbiota transfer, 16S sequencing, and inflammatory/AMP qRT-PCR","pmids":["39004000"],"confidence":"Medium","gaps":["Specific bacterial taxa and inflammatory signaling axis not defined","Co-housing only partially restores inflammation, leaving microbiota-independent contributions unquantified"]},{"year":2025,"claim":"Identified an upstream epigenetic mechanism controlling CLDN7 expression via histone crotonylation, connecting a metabolic acyl-CoA pathway to barrier maintenance.","evidence":"Genetic/pharmacological ACSS2 inhibition, H4K12cr chromatin measurement at CLDN7 locus, crotonate rescue, and colitis model","pmids":["40650658"],"confidence":"Medium","gaps":["Whether H4K12cr acts directly versus through intermediary factors not resolved","Single lab; no independent confirmation of the ACSS2-CLDN7 axis"]},{"year":2018,"claim":"Revealed a context-dependent oncogenic role, with CLDN7 overexpression driving proliferation, invasion, and EMT in gastric cancer.","evidence":"Gain- and loss-of-function in gastric cancer cell lines with proliferation, invasion, and EMT marker assays","pmids":["29788731"],"confidence":"Medium","gaps":["Molecular mechanism linking CLDN7 to EMT not defined","Cell-line only; no in vivo validation"]},{"year":2020,"claim":"Defined a post-transcriptional control point, establishing CLDN7 as a direct miR-1193 target mediating tumor-suppressive effects in cervical cancer.","evidence":"3'UTR luciferase reporter, qRT-PCR/Western, proliferation/migration/invasion assays, and CLDN7 rescue in miR-1193-overexpressing cells","pmids":["32547067"],"confidence":"Medium","gaps":["Does not explain how CLDN7 mechanistically drives the malignant phenotype downstream","Single lab; cell-line only"]},{"year":2026,"claim":"Connected CLDN7 to chemoresistance, showing it promotes cisplatin resistance through regulation of autophagy/mitophagy in ovarian cancer.","evidence":"siRNA knockdown in SKOV3/DDP cells, LC3/MitoTracker immunofluorescence, mitophagy marker Western blot, cisplatin sensitivity assays, and xenografts","pmids":["42057112"],"confidence":"Medium","gaps":["Molecular link between CLDN7 and the mitophagy machinery not identified","Whether this reflects a tight-junction-dependent or independent function is unknown"]},{"year":null,"claim":"How CLDN7 switches between barrier-protective (tumor-suppressive) and oncogenic functions across tissue contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism reconciling intestinal barrier protection with pro-invasive cancer roles","Direct claudin junction partners and channel properties not characterized in this corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]}],"pathway":[],"complexes":["tight junction"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95471","full_name":"Claudin-7","aliases":[],"length_aa":211,"mass_kda":22.4,"function":"Plays a major role in tight junction-specific obliteration of the intercellular space","subcellular_location":"Cell membrane; Basolateral cell membrane; Cell junction, tight junction","url":"https://www.uniprot.org/uniprotkb/O95471/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CLDN7","classification":"Not Classified","n_dependent_lines":12,"n_total_lines":1208,"dependency_fraction":0.009933774834437087},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CLDN7","total_profiled":1310},"omim":[{"mim_id":"609131","title":"CLAUDIN 7; CLDN7","url":"https://www.omim.org/entry/609131"},{"mim_id":"603718","title":"CLAUDIN 1; CLDN1","url":"https://www.omim.org/entry/603718"},{"mim_id":"602910","title":"CLAUDIN 3; CLDN3","url":"https://www.omim.org/entry/602910"},{"mim_id":"602909","title":"CLAUDIN 4; CLDN4","url":"https://www.omim.org/entry/602909"},{"mim_id":"602101","title":"CLAUDIN 5; CLDN5","url":"https://www.omim.org/entry/602101"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":324.6},{"tissue":"intestine","ntpm":321.6}],"url":"https://www.proteinatlas.org/search/CLDN7"},"hgnc":{"alias_symbol":["Hs.84359"],"prev_symbol":["CEPTRL2","CPETRL2"]},"alphafold":{"accession":"O95471","domains":[{"cath_id":"1.20.140.150","chopping":"1-30_75-183","consensus_level":"high","plddt":90.2201,"start":1,"end":183}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95471","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95471-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95471-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CLDN7","jax_strain_url":"https://www.jax.org/strain/search?query=CLDN7"},"sequence":{"accession":"O95471","fasta_url":"https://rest.uniprot.org/uniprotkb/O95471.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95471/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95471"}},"corpus_meta":[{"pmid":"34026335","id":"PMC_34026335","title":"Cldn-7 deficiency promotes experimental colitis and associated carcinogenesis by regulating intestinal epithelial integrity.","date":"2021","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/34026335","citation_count":43,"is_preprint":false},{"pmid":"31298324","id":"PMC_31298324","title":"Long noncoding RNA DDX11-AS1 induced by YY1 accelerates colorectal cancer progression through targeting miR-873/CLDN7 axis.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31298324","citation_count":29,"is_preprint":false},{"pmid":"29788731","id":"PMC_29788731","title":"Claudin-7 (CLDN7) is overexpressed in gastric cancer and promotes gastric cancer cell proliferation, invasion and maintains mesenchymal state.","date":"2018","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/29788731","citation_count":20,"is_preprint":false},{"pmid":"24479816","id":"PMC_24479816","title":"Polymorphisms in the CLDN1 and CLDN7 genes are related to differentiation and tumor stage in colon carcinoma.","date":"2014","source":"APMIS : acta pathologica, microbiologica, et immunologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/24479816","citation_count":14,"is_preprint":false},{"pmid":"32547067","id":"PMC_32547067","title":"MiR-1193 Inhibits the Malignancy of Cervical Cancer Cells by Targeting Claudin 7 (CLDN7).","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32547067","citation_count":10,"is_preprint":false},{"pmid":"25759378","id":"PMC_25759378","title":"A common variant in the CLDN7/ELP5 locus predicts adiponectin change with lifestyle intervention and improved fitness in obese individuals with diabetes.","date":"2015","source":"Physiological genomics","url":"https://pubmed.ncbi.nlm.nih.gov/25759378","citation_count":7,"is_preprint":false},{"pmid":"39175074","id":"PMC_39175074","title":"Expression and clinical significance of CLDN7 and its immune-related cells in breast cancer.","date":"2024","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39175074","citation_count":6,"is_preprint":false},{"pmid":"40650658","id":"PMC_40650658","title":"ACSS2-Mediated Histone H4 Lysine 12 Crotonylation (H4K12cr) Alleviates Colitis via Enhancing Transcription of CLDN7.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40650658","citation_count":6,"is_preprint":false},{"pmid":"39004000","id":"PMC_39004000","title":"Intestinal epithelial Cldn-7 regulates intestinal inflammation by altering the gut microbiota.","date":"2024","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/39004000","citation_count":4,"is_preprint":false},{"pmid":"38575994","id":"PMC_38575994","title":"Ginger inhibits the invasion of ovarian cancer cells SKOV3 through CLDN7, CLDN11 and CD274 m6A methylation modifications.","date":"2024","source":"BMC complementary medicine and therapies","url":"https://pubmed.ncbi.nlm.nih.gov/38575994","citation_count":2,"is_preprint":false},{"pmid":"42057112","id":"PMC_42057112","title":"Knocking down CLDN7 enhanced the effect of cisplatin in OC cells by regulating mitophagy.","date":"2026","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/42057112","citation_count":0,"is_preprint":false},{"pmid":"41789662","id":"PMC_41789662","title":"CLDN7: Epithelial gatekeeper from physiology to pathology‑roles in cancer and epithelial‑related diseases (Review).","date":"2026","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41789662","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.16.654558","title":"Clinical isolates of  <i>Fusobacterium nucleatum</i>  display strain-specific virulence and modulation by indole derivatives","date":"2025-05-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.16.654558","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.05.636626","title":"Sex-dependent effects of intestinal epithelial TLR4 deletion induced before activity-based anorexia","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.05.636626","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10552,"output_tokens":1690,"usd":0.028503,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8561,"output_tokens":2265,"usd":0.049715,"stage2_stop_reason":"end_turn"},"total_usd":0.078218,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"Intestinal epithelial Cldn-7 knockout (Cldn7fl/fl;villin-CreERT2 mice) disrupts tight junction integrity, increases intercellular permeability, and promotes susceptibility to experimental colitis and colitis-associated carcinogenesis, with activation of Wnt/β-catenin signaling in the tumor context.\",\n      \"method\": \"Inducible intestinal conditional knockout mouse model with AOM/DSS-induced colitis and CAC; FITC-dextran permeability assay; histology; immunostaining for β-catenin/TCF/LEF pathway components\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined cellular and molecular phenotypes (barrier permeability, Wnt pathway activation), multiple readouts, in vivo model\",\n      \"pmids\": [\"34026335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cldn-7 deficiency in intestinal epithelial cells alters gut microbiota composition (diversity and abundance) and this dysbiosis mediates intestinal inflammation; antibiotic-induced microbiota depletion reduces colitis severity in Cldn-7 KO mice, and co-housing (microbiota transfer) partially restores inflammation, placing Cldn-7 upstream of microbiota-mediated inflammatory signaling.\",\n      \"method\": \"Inducible intestinal conditional Cldn-7 KO mice; antibiotic treatment; co-housing experiment; 16S rRNA amplicon sequencing; qRT-PCR for inflammatory factors and AMPs; AB-PAS/Muc2 staining for mucus layer\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with epistasis-style antibiotic/co-housing rescue experiments and microbiome sequencing, single lab\",\n      \"pmids\": [\"39004000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ACSS2-mediated histone H4 lysine 12 crotonylation (H4K12cr) upregulates CLDN7 transcription to fortify the intestinal epithelial barrier; ACSS2 inhibition reduces H4K12cr at the CLDN7 locus, decreasing its expression and impairing barrier integrity, while crotonate supplementation augments this pathway.\",\n      \"method\": \"Genetic/pharmacological ACSS2 inhibition in mice; chromatin studies (H4K12cr at CLDN7 locus); crotonate supplementation rescue; intestinal barrier integrity assays; colitis model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established with genetic inhibition, histone modification measurement, and rescue by crotonate; single lab\",\n      \"pmids\": [\"40650658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CLDN7 overexpression in gastric cancer cells promotes cell proliferation, invasion, and maintenance of the mesenchymal state (epithelial-mesenchymal transition), indicating an oncogenic function for CLDN7 in this context.\",\n      \"method\": \"CLDN7 gain- and loss-of-function in gastric cancer cell lines; proliferation, invasion, and EMT marker assays\",\n      \"journal\": \"Neoplasma\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional cell-line KD/OE with defined phenotypic readouts (proliferation, invasion, EMT markers), single lab\",\n      \"pmids\": [\"29788731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CLDN7 is a direct transcriptional target of miR-1193 in cervical cancer cells; miR-1193 overexpression suppresses proliferation, invasion, and migration, and restoration of CLDN7 rescues these tumor-suppressing effects, confirming CLDN7 acts downstream of miR-1193.\",\n      \"method\": \"Luciferase reporter assay (3'UTR); qRT-PCR and Western blot; CCK-8, transwell, and wound-healing assays; CLDN7 rescue experiment in miR-1193-overexpressing cells\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms direct miRNA-target interaction; rescue experiment establishes epistasis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32547067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CLDN7 is preferentially localized to the cytoplasmic membrane of ovarian cancer cells; knockdown of CLDN7 in cisplatin-resistant SKOV3/DDP cells decreases autophagy and mitophagy (LC3, mitophagy markers), reduces migration and invasion, and enhances cisplatin sensitivity both in vitro and in xenograft models, indicating CLDN7 promotes cisplatin resistance through regulation of mitophagy.\",\n      \"method\": \"siRNA knockdown; Western blot for autophagy/mitophagy markers; immunofluorescence colocalization (LC3/MitoTracker); CCK-8 cisplatin sensitivity; transwell migration/invasion; xenograft tumor growth assay\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with multiple orthogonal methods including in vivo xenograft; single lab\",\n      \"pmids\": [\"42057112\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CLDN7 is a tight junction transmembrane protein that maintains intestinal epithelial barrier integrity and cell polarity; its loss disrupts paracellular permeability, dysregulates gut microbiota, and triggers inflammatory and Wnt/β-catenin-driven tumorigenic cascades, while its transcription is epigenetically regulated by ACSS2-mediated H4K12 crotonylation and post-transcriptionally by miR-1193; in cancer contexts CLDN7 can act oncogenically by promoting EMT, invasion, and cisplatin resistance via mitophagy regulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CLDN7 is a tight junction component that maintains intestinal epithelial barrier integrity, with its loss disrupting paracellular permeability and predisposing to inflammation and tumorigenesis [#0]. Conditional intestinal knockout compromises tight junction integrity, raises intercellular permeability, and promotes susceptibility to experimental colitis and colitis-associated carcinogenesis with activation of Wnt/\\u03b2-catenin signaling [#0]; barrier loss also reshapes gut microbiota composition, and this dysbiosis is itself a driver of the resulting inflammation, as antibiotic depletion attenuates and microbiota transfer restores colitis severity in knockout mice [#1]. CLDN7 transcription is reinforced epigenetically through ACSS2-mediated histone H4K12 crotonylation at the CLDN7 locus, a pathway augmented by crotonate that fortifies the barrier [#2]. In cancer contexts CLDN7 instead behaves oncogenically: it is a direct target of the tumor-suppressive miR-1193 in cervical cancer [#4], its overexpression drives proliferation, invasion, and epithelial-mesenchymal transition in gastric cancer [#3], and in cisplatin-resistant ovarian cancer cells it promotes autophagy/mitophagy, migration, invasion, and chemoresistance [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that intestinal CLDN7 is required for tight junction barrier integrity and that its loss links barrier failure to inflammation and Wnt-driven carcinogenesis.\",\n      \"evidence\": \"Inducible intestinal conditional knockout mice with AOM/DSS colitis/CAC, FITC-dextran permeability, and \\u03b2-catenin/TCF/LEF immunostaining\",\n      \"pmids\": [\"34026335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve whether Wnt activation is a direct consequence of CLDN7 loss or secondary to barrier breach\", \"No structural or claudin-channel mechanism for the permeability defect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed CLDN7 upstream of microbiota-mediated inflammation, showing that barrier loss-induced dysbiosis is causally required for the inflammatory phenotype.\",\n      \"evidence\": \"Conditional KO mice with antibiotic depletion, co-housing microbiota transfer, 16S sequencing, and inflammatory/AMP qRT-PCR\",\n      \"pmids\": [\"39004000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific bacterial taxa and inflammatory signaling axis not defined\", \"Co-housing only partially restores inflammation, leaving microbiota-independent contributions unquantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an upstream epigenetic mechanism controlling CLDN7 expression via histone crotonylation, connecting a metabolic acyl-CoA pathway to barrier maintenance.\",\n      \"evidence\": \"Genetic/pharmacological ACSS2 inhibition, H4K12cr chromatin measurement at CLDN7 locus, crotonate rescue, and colitis model\",\n      \"pmids\": [\"40650658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether H4K12cr acts directly versus through intermediary factors not resolved\", \"Single lab; no independent confirmation of the ACSS2-CLDN7 axis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a context-dependent oncogenic role, with CLDN7 overexpression driving proliferation, invasion, and EMT in gastric cancer.\",\n      \"evidence\": \"Gain- and loss-of-function in gastric cancer cell lines with proliferation, invasion, and EMT marker assays\",\n      \"pmids\": [\"29788731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking CLDN7 to EMT not defined\", \"Cell-line only; no in vivo validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a post-transcriptional control point, establishing CLDN7 as a direct miR-1193 target mediating tumor-suppressive effects in cervical cancer.\",\n      \"evidence\": \"3'UTR luciferase reporter, qRT-PCR/Western, proliferation/migration/invasion assays, and CLDN7 rescue in miR-1193-overexpressing cells\",\n      \"pmids\": [\"32547067\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not explain how CLDN7 mechanistically drives the malignant phenotype downstream\", \"Single lab; cell-line only\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected CLDN7 to chemoresistance, showing it promotes cisplatin resistance through regulation of autophagy/mitophagy in ovarian cancer.\",\n      \"evidence\": \"siRNA knockdown in SKOV3/DDP cells, LC3/MitoTracker immunofluorescence, mitophagy marker Western blot, cisplatin sensitivity assays, and xenografts\",\n      \"pmids\": [\"42057112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between CLDN7 and the mitophagy machinery not identified\", \"Whether this reflects a tight-junction-dependent or independent function is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CLDN7 switches between barrier-protective (tumor-suppressive) and oncogenic functions across tissue contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism reconciling intestinal barrier protection with pro-invasive cancer roles\", \"Direct claudin junction partners and channel properties not characterized in this corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\"tight junction\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}