{"gene":"CTSV","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2013,"finding":"CTSV (CTSL2) is a direct transcriptional target of E2F1: E2F1 binds the CTSL2 promoter directly, and RNAi-mediated depletion of CTSL2 abrogated E2F1-induced apoptosis coupled with reduced lysosomal membrane permeabilization (LMP) and mitochondrial membrane depolarization. CTSL2 knockdown also inhibited DNA damage-activated endogenous E2F1-mediated apoptosis, and CTSL2 depletion reduced histone deacetylase inhibitor (HDACi)-induced apoptosis while overexpression sensitized cells to HDACi.","method":"ChIP (E2F1 binding to CTSL2 promoter), RNAi knockdown with apoptosis/LMP/mitochondrial membrane readouts, ectopic overexpression in cancer cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal promoter binding by ChIP, RNAi loss-of-function with multiple orthogonal phenotypic readouts (apoptosis, LMP, mitochondrial depolarization), and gain-of-function, single lab","pmids":["23542171"],"is_preprint":false},{"year":2022,"finding":"CTSV promotes bladder cancer cell proliferation through activation of the NF-κB signaling pathway; overexpression of CTSV increased NF-κB transcriptional activity measured by luciferase reporter assay, and this effect was reversed by an NF-κB inhibitor. CTSV deletion inhibited proliferation in vitro and tumor growth in vivo.","method":"Dual-luciferase reporter assay for NF-κB activity, CCK8/colony formation assays, siRNA knockdown, overexpression, xenograft mouse model","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter and in vivo validation with loss/gain-of-function, single lab, pathway placement via pharmacological inhibitor rescue","pmids":["35443863"],"is_preprint":false},{"year":2020,"finding":"CTSV expression in renal carcinoma cells is regulated downstream of the EGFR-MEK-ERK signaling pathway: EGF treatment upregulated CTSV mRNA and protein, and inhibition of EGFR-MEK-ERK signaling (by Praeruptorin B or pathway-specific inhibitors) suppressed CTSV expression, migration, and invasion.","method":"Western blotting, RT-PCR, EGF stimulation/inhibition experiments, pharmacological inhibition of EGFR-MEK-ERK pathway in RCC cell lines","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway placement by pharmacological inhibition and ligand stimulation, single lab, two cell lines tested","pmids":["32331211"],"is_preprint":false},{"year":2025,"finding":"CTSV expression in colorectal cancer cells is regulated via a PKCα/PKCδ-ERK-Sp1 transcriptional axis: TCD inhibited PKC and ERK phosphorylation, reduced Sp1 transcriptional activity, and thereby suppressed CTSV expression; siRNA knockdown of ERK or CTSV enhanced anti-migratory effects, and PKC activator (TPA) rescued CTSV expression and migration that TCD suppressed.","method":"siRNA knockdown of ERK and CTSV, human protease array, immunoblot for phospho-PKCα/PKCδ/ERK/Sp1, PKC activator (TPA) rescue experiment, migration/invasion assays","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pathway placement using siRNA and pharmacological rescue, proteomic array, single lab with multiple orthogonal approaches","pmids":["40674912"],"is_preprint":false}],"current_model":"CTSV (cathepsin V/CTSL2) is a lysosomal cysteine protease that functions as a direct E2F1 transcriptional target to promote lysosomal membrane permeabilization and apoptosis; its expression is regulated upstream by EGFR-MEK-ERK and PKC-ERK-Sp1 signaling axes, and it promotes cancer cell proliferation and NF-κB activity downstream."},"narrative":{"mechanistic_narrative":"CTSV (cathepsin V/CTSL2) is a cysteine protease that acts both as an executioner of apoptosis and a driver of cancer cell proliferation, integrating transcriptional inputs from oncogenic signaling pathways [PMID:23542171, PMID:35443863]. It is a direct transcriptional target of E2F1, which binds the CTSL2 promoter and requires CTSV to execute apoptosis through lysosomal membrane permeabilization and downstream mitochondrial membrane depolarization; CTSV is likewise required for DNA-damage- and HDAC-inhibitor-induced apoptosis, and its overexpression sensitizes cells to HDAC inhibitors [PMID:23542171]. In a proliferative context, CTSV drives bladder cancer cell growth and xenograft tumor formation through activation of NF-κB transcriptional activity [PMID:35443863]. CTSV expression is controlled by upstream oncogenic signaling: an EGFR-MEK-ERK axis upregulates CTSV to promote renal carcinoma migration and invasion [PMID:32331211], and a PKCα/PKCδ-ERK-Sp1 transcriptional axis governs CTSV expression and migratory behavior in colorectal cancer [PMID:40674912]. Beyond these transcriptional and pathway-placement findings, the catalytic substrates and structural basis of CTSV protease activity have not been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Established CTSV as a direct effector arm of E2F1-driven apoptosis, answering how a transcription factor couples to the lysosomal-mitochondrial death machinery.","evidence":"ChIP of E2F1 at the CTSL2 promoter plus RNAi loss-of-function and overexpression with apoptosis, LMP, and mitochondrial depolarization readouts in cancer cells","pmids":["23542171"],"confidence":"High","gaps":["No protease substrate identified that links CTSV activity to LMP","Mechanism by which CTSV triggers lysosomal membrane permeabilization is not resolved","Single-lab; cell-line dependence of the apoptotic role untested broadly"]},{"year":2020,"claim":"Placed CTSV downstream of EGFR-MEK-ERK signaling, identifying an upstream pathway that controls its expression and links it to invasion.","evidence":"EGF stimulation and pharmacological/pathway-specific inhibition with Western blot and RT-PCR in RCC cell lines, plus migration/invasion assays","pmids":["32331211"],"confidence":"Medium","gaps":["Pathway placement rests on pharmacological inhibition; direct transcriptional mechanism not defined","Only two cell lines tested","Does not connect ERK regulation to the E2F1/apoptotic role"]},{"year":2022,"claim":"Defined a downstream pro-proliferative output for CTSV via NF-κB activation, contrasting with its pro-apoptotic role and implicating it in tumor growth.","evidence":"Dual-luciferase NF-κB reporter with inhibitor rescue, siRNA/overexpression proliferation assays, and xenograft mouse model in bladder cancer","pmids":["35443863"],"confidence":"Medium","gaps":["How CTSV protease activity activates NF-κB is not mechanistically defined","Pathway placement relies on a pharmacological NF-κB inhibitor","Reconciliation of pro-apoptotic vs pro-proliferative roles unaddressed"]},{"year":2025,"claim":"Identified a PKCα/PKCδ-ERK-Sp1 transcriptional axis controlling CTSV expression and migration, extending upstream regulatory understanding into colorectal cancer.","evidence":"siRNA knockdown of ERK and CTSV, protease array, phospho-immunoblots, and TPA rescue with migration/invasion assays","pmids":["40674912"],"confidence":"Medium","gaps":["Sp1 binding to the CTSV promoter inferred from activity, not direct binding assay here","Single-lab pharmacological/siRNA approach","Relationship to the EGFR-MEK-ERK axis not directly compared"]},{"year":null,"claim":"The endogenous catalytic substrates, structural basis, and subcellular site of CTSV protease action that mechanistically explain its apoptotic and pro-tumorigenic effects remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No CTSV proteolytic substrate identified in the corpus","Mechanism linking protease activity to LMP and to NF-κB activation unknown","No structural or enzymatic characterization in the timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60911","full_name":"Cathepsin L2","aliases":["Cathepsin U","Cathepsin V"],"length_aa":334,"mass_kda":37.3,"function":"Cysteine protease. May have an important role in corneal physiology","subcellular_location":"Lysosome","url":"https://www.uniprot.org/uniprotkb/O60911/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CTSV","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PMVK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CTSV","total_profiled":1310},"omim":[{"mim_id":"609812","title":"MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 8, WITH EXOCRINE DYSFUNCTION; MODY8","url":"https://www.omim.org/entry/609812"},{"mim_id":"603308","title":"CATHEPSIN V; CTSV","url":"https://www.omim.org/entry/603308"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":599.5}],"url":"https://www.proteinatlas.org/search/CTSV"},"hgnc":{"alias_symbol":["CTSU"],"prev_symbol":["CTSL2"]},"alphafold":{"accession":"O60911","domains":[{"cath_id":"3.90.70.10","chopping":"90-334","consensus_level":"high","plddt":95.4263,"start":90,"end":334},{"cath_id":"1.10.287","chopping":"24-72","consensus_level":"high","plddt":96.2943,"start":24,"end":72}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60911","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60911-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60911-F1-predicted_aligned_error_v6.png","plddt_mean":92.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CTSV","jax_strain_url":"https://www.jax.org/strain/search?query=CTSV"},"sequence":{"accession":"O60911","fasta_url":"https://rest.uniprot.org/uniprotkb/O60911.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60911/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60911"}},"corpus_meta":[{"pmid":"17869649","id":"PMC_17869649","title":"Polymorphisms in the cathepsin L2 (CTSL2) gene show association with type 1 diabetes and early-onset myasthenia gravis.","date":"2007","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17869649","citation_count":28,"is_preprint":false},{"pmid":"35443863","id":"PMC_35443863","title":"CTSV (cathepsin V) promotes bladder cancer progression by increasing NF-κB activity.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35443863","citation_count":18,"is_preprint":false},{"pmid":"32331211","id":"PMC_32331211","title":"Praeruptorin B Mitigates the Metastatic Ability of Human Renal Carcinoma Cells through Targeting CTSC and CTSV Expression.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32331211","citation_count":18,"is_preprint":false},{"pmid":"23542171","id":"PMC_23542171","title":"CTSL2 is a pro-apoptotic target of E2F1 and a modulator of histone deacetylase inhibitor and DNA damage-induced apoptosis.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23542171","citation_count":7,"is_preprint":false},{"pmid":"17934903","id":"PMC_17934903","title":"Evaluation of the CTSL2 gene as a candidate gene for alopecia X in Pomeranians and Keeshonden.","date":"2007","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/17934903","citation_count":7,"is_preprint":false},{"pmid":"40674912","id":"PMC_40674912","title":"Trichodermin, an endophytic fungal sesquiterpene, suppresses colorectal cancer cell migration and invasion by targeting the PKC-ERK-Sp1-CTSV axis.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40674912","citation_count":1,"is_preprint":false},{"pmid":"40275325","id":"PMC_40275325","title":"CTSL-2 upon specifically recognizing Vibrio splendidus directly cleaves complement C3 to promote the bacterial phagocytosis and degradation in oyster.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/40275325","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.08.01.668211","title":"A parenchymal niche regulates pluripotent stem cell function in planarians","date":"2025-08-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.01.668211","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.26.690782","title":"Benchmarking Cell-Type-Specific Spatially Variable Gene Detection Methods Using a Realistic and Decomposable Simulation Framework","date":"2025-12-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.26.690782","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6561,"output_tokens":1885,"usd":0.023979,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7883,"output_tokens":1993,"usd":0.04462,"stage2_stop_reason":"end_turn"},"total_usd":0.068599,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"I need to carefully evaluate each paper:\n\n1. **[1] PMID:17869649** - CTSL2 (=CTSV) polymorphism study. The abstract mentions CTSV \"involved in antigen presentation in human cortical thymic epithelial cells\" but this is stated as background, not an experiment in this paper. The paper itself does genetic association only. EXCLUDE mechanistic finding.\n\n2. **[2] PMID:35443863** - CTSV promotes bladder cancer via NF-κB. Dual-luciferase reporter assay shows CTSV overexpression activates NF-κB pathway; NF-κB inhibitor restores this. Loss-of-function experiments. INCLUDE.\n\n3. **[3] PMID:32331211** - Pra-B downregulates CTSV via EGFR-MEK-ERK pathway in RCC. Shows CTSV expression is regulated by EGFR-MEK-ERK signaling. INCLUDE (pathway placement of CTSV downstream of EGFR-MEK-ERK).\n\n4. **[4] PMID:23542171** - CTSL2 (=CTSV) is an E2F1 target; E2F1 binds CTSL2 promoter; CTSL2 mediates LMP and apoptosis. ChIP, RNAi, functional apoptosis assays. INCLUDE - strong mechanistic findings.\n\n5. **[5] PMID:17934903** - Dog alopecia X study, negative association. EXCLUDE (negative/no mechanism).\n\n6. **[6] PMID:40674912** - TCD suppresses CRC via PKC-ERK-Sp1-CTSV axis. siRNA knockdown, proteomic array, signaling pathway. INCLUDE.\n\n7. **[7] PMID:40275325** - Oyster CTSL-2 (CgCTSL-2). This is an oyster (Crassostrea gigas) gene, not a mammalian ortholog. The function described (complement C3 cleavage, bacterial recognition) is fundamentally different from the mammalian CTSV context. EXCLUDE as symbol collision.\n\n8. **[8] bio_10.1101_2025.08.01.668211** - Planarian CTSL2. This is a planarian gene, not the human CTSV ortholog. EXCLUDE as cross-kingdom collision.\n\n9. **[9] bio_10.1101_2025.11.26.690782** - \"CTSV\" here refers to a computational method (algorithm), not the gene. EXCLUDE.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"CTSV (CTSL2) is a direct transcriptional target of E2F1: E2F1 binds the CTSL2 promoter directly, and RNAi-mediated depletion of CTSL2 abrogated E2F1-induced apoptosis coupled with reduced lysosomal membrane permeabilization (LMP) and mitochondrial membrane depolarization. CTSL2 knockdown also inhibited DNA damage-activated endogenous E2F1-mediated apoptosis, and CTSL2 depletion reduced histone deacetylase inhibitor (HDACi)-induced apoptosis while overexpression sensitized cells to HDACi.\",\n      \"method\": \"ChIP (E2F1 binding to CTSL2 promoter), RNAi knockdown with apoptosis/LMP/mitochondrial membrane readouts, ectopic overexpression in cancer cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal promoter binding by ChIP, RNAi loss-of-function with multiple orthogonal phenotypic readouts (apoptosis, LMP, mitochondrial depolarization), and gain-of-function, single lab\",\n      \"pmids\": [\"23542171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CTSV promotes bladder cancer cell proliferation through activation of the NF-κB signaling pathway; overexpression of CTSV increased NF-κB transcriptional activity measured by luciferase reporter assay, and this effect was reversed by an NF-κB inhibitor. CTSV deletion inhibited proliferation in vitro and tumor growth in vivo.\",\n      \"method\": \"Dual-luciferase reporter assay for NF-κB activity, CCK8/colony formation assays, siRNA knockdown, overexpression, xenograft mouse model\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter and in vivo validation with loss/gain-of-function, single lab, pathway placement via pharmacological inhibitor rescue\",\n      \"pmids\": [\"35443863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CTSV expression in renal carcinoma cells is regulated downstream of the EGFR-MEK-ERK signaling pathway: EGF treatment upregulated CTSV mRNA and protein, and inhibition of EGFR-MEK-ERK signaling (by Praeruptorin B or pathway-specific inhibitors) suppressed CTSV expression, migration, and invasion.\",\n      \"method\": \"Western blotting, RT-PCR, EGF stimulation/inhibition experiments, pharmacological inhibition of EGFR-MEK-ERK pathway in RCC cell lines\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway placement by pharmacological inhibition and ligand stimulation, single lab, two cell lines tested\",\n      \"pmids\": [\"32331211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CTSV expression in colorectal cancer cells is regulated via a PKCα/PKCδ-ERK-Sp1 transcriptional axis: TCD inhibited PKC and ERK phosphorylation, reduced Sp1 transcriptional activity, and thereby suppressed CTSV expression; siRNA knockdown of ERK or CTSV enhanced anti-migratory effects, and PKC activator (TPA) rescued CTSV expression and migration that TCD suppressed.\",\n      \"method\": \"siRNA knockdown of ERK and CTSV, human protease array, immunoblot for phospho-PKCα/PKCδ/ERK/Sp1, PKC activator (TPA) rescue experiment, migration/invasion assays\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pathway placement using siRNA and pharmacological rescue, proteomic array, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"40674912\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTSV (cathepsin V/CTSL2) is a lysosomal cysteine protease that functions as a direct E2F1 transcriptional target to promote lysosomal membrane permeabilization and apoptosis; its expression is regulated upstream by EGFR-MEK-ERK and PKC-ERK-Sp1 signaling axes, and it promotes cancer cell proliferation and NF-κB activity downstream.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTSV (cathepsin V/CTSL2) is a cysteine protease that acts both as an executioner of apoptosis and a driver of cancer cell proliferation, integrating transcriptional inputs from oncogenic signaling pathways [#0, #1]. It is a direct transcriptional target of E2F1, which binds the CTSL2 promoter and requires CTSV to execute apoptosis through lysosomal membrane permeabilization and downstream mitochondrial membrane depolarization; CTSV is likewise required for DNA-damage- and HDAC-inhibitor-induced apoptosis, and its overexpression sensitizes cells to HDAC inhibitors [#0]. In a proliferative context, CTSV drives bladder cancer cell growth and xenograft tumor formation through activation of NF-\\u03baB transcriptional activity [#1]. CTSV expression is controlled by upstream oncogenic signaling: an EGFR-MEK-ERK axis upregulates CTSV to promote renal carcinoma migration and invasion [#2], and a PKC\\u03b1/PKC\\u03b4-ERK-Sp1 transcriptional axis governs CTSV expression and migratory behavior in colorectal cancer [#3]. Beyond these transcriptional and pathway-placement findings, the catalytic substrates and structural basis of CTSV protease activity have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established CTSV as a direct effector arm of E2F1-driven apoptosis, answering how a transcription factor couples to the lysosomal-mitochondrial death machinery.\",\n      \"evidence\": \"ChIP of E2F1 at the CTSL2 promoter plus RNAi loss-of-function and overexpression with apoptosis, LMP, and mitochondrial depolarization readouts in cancer cells\",\n      \"pmids\": [\"23542171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No protease substrate identified that links CTSV activity to LMP\",\n        \"Mechanism by which CTSV triggers lysosomal membrane permeabilization is not resolved\",\n        \"Single-lab; cell-line dependence of the apoptotic role untested broadly\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed CTSV downstream of EGFR-MEK-ERK signaling, identifying an upstream pathway that controls its expression and links it to invasion.\",\n      \"evidence\": \"EGF stimulation and pharmacological/pathway-specific inhibition with Western blot and RT-PCR in RCC cell lines, plus migration/invasion assays\",\n      \"pmids\": [\"32331211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Pathway placement rests on pharmacological inhibition; direct transcriptional mechanism not defined\",\n        \"Only two cell lines tested\",\n        \"Does not connect ERK regulation to the E2F1/apoptotic role\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a downstream pro-proliferative output for CTSV via NF-\\u03baB activation, contrasting with its pro-apoptotic role and implicating it in tumor growth.\",\n      \"evidence\": \"Dual-luciferase NF-\\u03baB reporter with inhibitor rescue, siRNA/overexpression proliferation assays, and xenograft mouse model in bladder cancer\",\n      \"pmids\": [\"35443863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How CTSV protease activity activates NF-\\u03baB is not mechanistically defined\",\n        \"Pathway placement relies on a pharmacological NF-\\u03baB inhibitor\",\n        \"Reconciliation of pro-apoptotic vs pro-proliferative roles unaddressed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified a PKC\\u03b1/PKC\\u03b4-ERK-Sp1 transcriptional axis controlling CTSV expression and migration, extending upstream regulatory understanding into colorectal cancer.\",\n      \"evidence\": \"siRNA knockdown of ERK and CTSV, protease array, phospho-immunoblots, and TPA rescue with migration/invasion assays\",\n      \"pmids\": [\"40674912\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Sp1 binding to the CTSV promoter inferred from activity, not direct binding assay here\",\n        \"Single-lab pharmacological/siRNA approach\",\n        \"Relationship to the EGFR-MEK-ERK axis not directly compared\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous catalytic substrates, structural basis, and subcellular site of CTSV protease action that mechanistically explain its apoptotic and pro-tumorigenic effects remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No CTSV proteolytic substrate identified in the corpus\",\n        \"Mechanism linking protease activity to LMP and to NF-\\u03baB activation unknown\",\n        \"No structural or enzymatic characterization in the timeline\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}