{"gene":"KLK7","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2004,"finding":"KLK7 (SCCE) directly cleaves corneodesmosin (CDSN) and desmocollin 1 (DSC1) at acidic pH, but is unable to degrade desmoglein 1 (DSG1). Oligosaccharide residues on CDSN do not protect it against KLK7 proteolysis. KLK5 (SCTE) can activate the proform of KLK7, suggesting a protease cascade in desquamation.","method":"In vitro protease activity assay with recombinant and epidermal protein substrates; enzymatic deglycosylation experiments; proenzyme activation assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution of substrate cleavage with multiple substrates and glycosylation controls, replicated across two proteases","pmids":["15140227"],"is_preprint":false},{"year":2007,"finding":"LEKTI fragments specifically inhibit KLK7 (as well as KLK5 and KLK14) in a pH-dependent manner; at acidic pH, active KLK5 is released from the LEKTI complex, allowing corneodesmosomal cleavage in superficial stratum corneum layers. The pH gradient of the epidermis thus governs the spatial regulation of KLK7 activity.","method":"Biochemical inhibition kinetics assays; pH-dependent binding/release experiments; analysis of LEKTI fragments generated by furin cleavage in cultured keratinocytes and epidermis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted inhibitor-protease kinetics with multiple LEKTI domain fragments, pH-dependent release demonstrated in vitro with functional validation","pmids":["17596512"],"is_preprint":false},{"year":2005,"finding":"In normal human epidermis, KLK7 and KLK5 are co-localized in lamellar granules but are spatially separated from LEKTI, which is packaged earlier. KLK7 secretion from lamellar granules into the extracellular space precedes that of the inhibitor, establishing a temporally regulated proteolytic system for desquamation.","method":"Confocal laser scanning microscopy and immunoelectron microscopy of normal and Netherton syndrome skin","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal immunolocalization with two orthogonal imaging methods (confocal + immunoelectron microscopy) in both normal and disease tissue","pmids":["15675955"],"is_preprint":false},{"year":2016,"finding":"In atopic dermatitis lesions, KLK7 secretion from lamellar granules is impaired despite elevated KLK7 protein levels; in situ zymography shows no significant elevation of KLK7 enzymatic activity at the corneocyte surface, and LEKTI expression is upregulated. This imbalance leads to abnormal corneodesmosin degradation patterns and compact hyperkeratosis.","method":"Western blot, in situ zymography of tape-stripped corneocytes, electron microscopy, immunostaining of AD and normal skin","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (zymography, western blot, EM, immunostaining) in a single lab establishing mechanistic dissociation between protein level and secreted enzymatic activity","pmids":["27769847"],"is_preprint":false},{"year":2022,"finding":"Inhibitory antibodies against KLK5 and KLK7, combined as a bispecific antibody (RO7449135), compensate for LEKTI deficiency in mouse models of Netherton syndrome and atopic dermatitis, restoring skin barrier integrity and reducing inflammation. A crystal structure of KLK5 with the inhibitory Fab revealed allosteric inhibition distal to the active site, establishing a non-competitive inhibitory mechanism.","method":"Crystal structure determination of KLK5-Fab complex; mouse models of NS and AD with antibody treatment; skin barrier function and inflammation assays","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation in multiple in vivo disease models, bispecific antibody engineering with mechanistic structural insight","pmids":["36516271"],"is_preprint":false},{"year":2017,"finding":"KLK7 exhibits chymotryptic-like cleavage preferences with a preference for hydrophobic residues at P2-P1 (non-prime) and hydrophilic residues at P1'-P2' (prime) subsites. Single active-site mutant KLK7 (S195A) retains residual catalytic activity, but the double mutant (S195A + D102N) achieves catalytic inactivity, establishing that standard single-mutant controls are insufficient for MS-based studies.","method":"Mass spectrometry-based PICS (Proteomic Identification of protease Cleavage Sites) with human proteome-derived peptide libraries; active-site mutagenesis (S195A single and S195A/D102N double mutants); kinetic assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and MS-based substrate profiling in a single rigorous study","pmids":["28754951"],"is_preprint":false},{"year":2019,"finding":"In the secretome of ovarian cancer cells (SKOV-3 and OVMZ-6), KLK7 directly activates pro-MMP10, cleaves IGFBP3 and IGFBP6, and cleaves thrombospondin 1 generating a potentially bioactive N-terminal fragment. Sixteen additional novel putative substrates were identified, enriched for cell adhesion, extracellular matrix remodeling, and cell migration functions.","method":"Quantitative proteomics (PROTOMAP + SILAC) and Terminal Amine Isotopic Labeling of Substrates (TAILS) in ovarian cancer cell secretomes; biochemical validation of specific substrates","journal":"Molecular & cellular proteomics : MCP","confidence":"High","confidence_rationale":"Tier 1 / Moderate — two technically orthogonal proteomics approaches plus biochemical validation of select substrates in a single rigorous study","pmids":["30705123"],"is_preprint":false},{"year":2024,"finding":"KLK7 undergoes autolysis at two sites in the 170 and 99 loops (chymotrypsinogen numbering), resulting in loss of enzymatic activity. KLK7 cleaves mast cell chymase, resulting in loss of chymase activity. KLK7 also hydrolyzes multiple cytokines including IFN-α, IFN-β, IFN-γ, IL-28A/IFN-λ2, IL-20, IL-22, and IL-27.","method":"Protease-specific inhibitor assays; active-site variant analysis; in vitro cleavage assays with recombinant chymase and cytokines; activity measurements","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution with inhibitors and variants, single lab, novel substrates but no in vivo validation","pmids":["39655764"],"is_preprint":false},{"year":2000,"finding":"KLK7 encodes a secreted chymotrypsin-like serine protease. Its expression is up-regulated by estrogens and glucocorticoids in the breast carcinoma cell line BT-474, identifying hormonal regulation of KLK7 expression.","method":"Northern blot; hormone treatment of BT-474 cells; genomic characterization and phylogenetic analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct hormonal induction measured by Northern blot in a single cell line, single lab","pmids":["10974542"],"is_preprint":false},{"year":2012,"finding":"Combined stable overexpression of KLK4, KLK5, KLK6, and KLK7 in ovarian cancer cells (OV-MZ-6) downregulates α5β1 and αvβ3 integrin expression, reduces adhesion to vitronectin and fibronectin, and increases resistance to paclitaxel (but not carboplatin). Paclitaxel resistance was not blocked by the MEK1/2 inhibitor U0126, indicating MAPK-independent mechanisms.","method":"Stable transfection with KLK expression plasmids; integrin quantification; adhesion assays; chemosensitivity assays; MEK1/2 inhibitor treatment; confocal microscopy","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple assays in a single lab but note: this is a combined KLK4-7 overexpression study, not KLK7 alone, limiting specificity of attribution","pmids":["22964375"],"is_preprint":false},{"year":2017,"finding":"Adipose tissue-specific knockout of KLK7 (ATKlk7−/−) in mice on high-fat diet results in less weight gain, preferential subcutaneous fat expansion, improved whole-body insulin sensitivity, higher energy expenditure, reduced pro-inflammatory cytokine expression, and increased anti-inflammatory M2 macrophage polarization in epididymal adipose tissue. These effects are associated with altered adipokine secretion including lower leptin.","method":"Conditional adipose-specific gene targeting (Cre/lox); metabolic phenotyping; cytokine quantification; macrophage FACS analysis; adipokine measurement","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with multiple orthogonal metabolic and immunological readouts, clear loss-of-function phenotype","pmids":["28932870"],"is_preprint":false},{"year":2025,"finding":"Macrophage-specific KLK7 knockout (KLK7MKO) in high-fat diet mice reduces systemic inflammation, decreases inflammatory macrophage infiltration and activation in epididymal adipose tissue, reduces pro-inflammatory gene expression in macrophages, and restricts macrophage migration by increasing cell adhesion. In human visceral adipose tissue (n=1143), KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression.","method":"Macrophage-specific Cre/lox KO; flow cytometry; gene expression analysis; migration/adhesion assays; human transcriptomic data analysis","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KO with multiple orthogonal functional readouts plus human transcriptomic validation","pmids":["40154838"],"is_preprint":false},{"year":2020,"finding":"IL-13 stimulation induces KLK7 transcription in keratinocytes via the ERK1/2 MAPK pathway activating the transcription factor EGR-1, which directly binds an EGR-1 binding sequence (EBS) in the KLK7 promoter. Point mutation of the EBS abrogates IL-13-induced KLK7 promoter activity; EGR1 knockdown abolishes KLK7 induction; and Egr1 knockout mice show reduced KLK7 expression in atopic dermatitis-like lesions.","method":"Promoter-luciferase reporter assay with point mutation of EBS; ChIP or direct binding assay for EGR-1 to EBS; shRNA knockdown of EGR1; Egr1 knockout mice with AD-like model; ERK1/2 inhibitor treatment","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reporter assay with mutagenesis, KD, and KO all converging on the same IL13-ERK-EGR1-KLK7 axis in a single study","pmids":["33276948"],"is_preprint":false},{"year":2025,"finding":"KLK5 and KLK7 drive HPV-dependent cervical carcinogenesis; absence of both KLK5 and KLK7 ameliorates the HPV-dependent phenotype. The mechanism operates via KLK14 activation, with KLK14 exerting pro-tumorigenic effects through PAR-2-dependent RhoA and NF-κB signaling pathways.","method":"Genetically engineered mice (KLK5/KLK7 double knockout); bulk RNA-seq; luciferase reporter assays; human biopsy analysis","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis in mouse model with reporter assay establishes pathway position, but KLK7-specific contribution is not separated from KLK5 in the mechanistic studies","pmids":["40753921"],"is_preprint":false},{"year":2025,"finding":"NF-κB signaling in astrocytes negatively regulates KLK7 mRNA expression; inhibition of NF-κB increases KLK7 expression and promotes amyloid-β (Aβ) degradation in astrocytes. In vivo, NF-κB inhibitor injection upregulates Klk7 expression and reduces Aβ levels, identifying KLK7 as an astrocyte-derived Aβ-degrading protease regulated by NMDA receptor-NF-κB signaling.","method":"NF-κB inhibitor treatment of astrocytes; KLK7 expression measurement; Aβ degradation assay; in vivo NF-κB inhibitor injection in mouse model; correlation analysis of NF-κB family and KLK7 in AD brain transcriptomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — preprint with in vitro and in vivo functional validation but single lab, not peer-reviewed","pmids":["bio_10.1101_2025.03.02.641088"],"is_preprint":true},{"year":2025,"finding":"Impaired store-operated Ca2+ entry (SOCE) via STIM1/2 knockout in mouse keratinocytes leads to elevated Klk7 levels and increased chymotrypsin-like serine protease activity at the epidermal surface, causing hyperkeratosis and impaired barrier function. Desmoglein 1 alterations are associated with excess KLK7 activity in this context.","method":"Epithelial-specific Stim1/2 double knockout mice; RNA-seq; in situ serine protease activity measurement; TEWL measurement; histology","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, KLK7 activation is a downstream consequence of SOCE loss rather than direct mechanistic study of KLK7 itself; indirect evidence","pmids":["bio_10.1101_2025.10.14.681588"],"is_preprint":true},{"year":2026,"finding":"Structure-guided development of KLK7 inhibitors using a published crystal structure identified the S1 binding pocket, where threonine 190 is a key selectivity determinant (vs. murine Klk7 which has threonine 190). Mutation T190A in murine Klk7 restores inhibitor sensitivity. Inhibitors block KLK7-mediated chemokine cleavage and moesin gene upregulation in ovarian cancer cells.","method":"Medicinal chemistry guided by published KLK7 crystal structure; Ki measurement; site-directed mutagenesis of T190A; functional assays (chemokine cleavage, moesin expression); xenograft mouse model","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structure-guided inhibitor design with mutagenesis confirming active site residue, functional validation in cells and in vivo, single lab","pmids":["41855304"],"is_preprint":false}],"current_model":"KLK7 is a secreted chymotrypsin-like serine protease that cleaves corneodesmosomal proteins (corneodesmosin, desmocollin 1) to drive epidermal desquamation; its activity is activated by KLK5 (via proenzyme cleavage), spatially and temporally controlled by the LEKTI inhibitor through a pH-dependent interaction in lamellar granules, transcriptionally regulated by the IL-13/ERK/EGR-1 axis in keratinocytes, and exerts additional roles in adipose tissue inflammation (controlling macrophage polarization and migration), amyloid-β clearance in astrocytes (negatively regulated by NF-κB), and cancer progression (via ECM remodeling, integrin downregulation, cytokine cleavage, and downstream activation of KLK14-PAR-2-RhoA/NF-κB signaling)."},"narrative":{"mechanistic_narrative":"KLK7 is a secreted chymotrypsin-like serine protease that drives epidermal desquamation by directly cleaving the corneodesmosomal proteins corneodesmosin (CDSN) and desmocollin 1 (DSC1) at acidic pH, while sparing desmoglein 1 [PMID:15140227]. Its catalysis follows a chymotryptic specificity, favoring hydrophobic residues at the non-prime subsites, and depends on the canonical Ser195/Asp102 catalytic dyad [PMID:28754951]. KLK7 operates within a tightly regulated proteolytic system: its proform is activated by KLK5 [PMID:15140227], and its activity is spatially and temporally constrained by the LEKTI inhibitor through a pH-dependent interaction, with KLK7 secreted from lamellar granules ahead of LEKTI and active enzyme released as the stratum corneum acidifies [PMID:17596512, PMID:15675955]. Disruption of this balance underlies barrier disease: impaired KLK7 secretion produces abnormal corneodesmosin degradation and compact hyperkeratosis in atopic dermatitis [PMID:27769847], and combined antibody inhibition of KLK5 and KLK7 compensates for LEKTI deficiency to restore the barrier in Netherton syndrome and atopic dermatitis models [PMID:36516271]. KLK7 transcription in keratinocytes is induced by IL-13 through an ERK1/2–EGR-1 axis acting on an EGR-1 binding site in the KLK7 promoter [PMID:33276948]. Beyond the skin, KLK7 cleaves a broad set of extracellular substrates—activating pro-MMP10, processing IGFBP3/6 and thrombospondin 1 in ovarian cancer secretomes [PMID:30705123], and hydrolyzing multiple cytokines and mast cell chymase [PMID:39655764]—and contributes to adipose tissue inflammation, where tissue- and macrophage-specific knockout reduces inflammatory macrophage activation, restricts macrophage migration by promoting adhesion, and improves metabolic outcomes [PMID:28932870, PMID:40154838].","teleology":[{"year":2000,"claim":"Establishing KLK7 as a secreted chymotrypsin-like serine protease and showing its expression is hormonally controlled framed it as a regulated, potentially disease-relevant enzyme.","evidence":"Northern blot and hormone treatment of BT-474 breast carcinoma cells with genomic characterization","pmids":["10974542"],"confidence":"Medium","gaps":["No physiological substrate identified at this stage","Hormonal induction shown in a single cancer cell line only"]},{"year":2004,"claim":"Identifying corneodesmosin and desmocollin 1 as direct substrates, and KLK5 as the activator of pro-KLK7, defined KLK7's role in a desquamation protease cascade.","evidence":"In vitro protease assays with recombinant and epidermal substrates, deglycosylation controls, and proenzyme activation assay","pmids":["15140227"],"confidence":"High","gaps":["In vitro cleavage does not establish in vivo rate-limiting roles","Did not address how activity is spatially confined in tissue"]},{"year":2005,"claim":"Showing that KLK7/KLK5 and LEKTI are differentially packaged and secreted from lamellar granules explained how proteolysis is temporally gated during corneocyte maturation.","evidence":"Confocal and immunoelectron microscopy of normal and Netherton syndrome skin","pmids":["15675955"],"confidence":"High","gaps":["Did not define the biochemical trigger for inhibitor release"]},{"year":2007,"claim":"Demonstrating pH-dependent LEKTI inhibition of KLK7 connected the epidermal pH gradient to the spatial activation of desquamatory proteolysis in superficial layers.","evidence":"Inhibition kinetics and pH-dependent binding/release assays with LEKTI fragments from keratinocytes","pmids":["17596512"],"confidence":"High","gaps":["Quantitative contribution of pH gradient in intact tissue not measured","Did not separate KLK7 from KLK5/KLK14 contributions to desquamation"]},{"year":2012,"claim":"Combined KLK4-7 overexpression in ovarian cancer cells linked these proteases to integrin downregulation, reduced ECM adhesion, and chemoresistance, suggesting a tumor-modifying role.","evidence":"Stable transfection, integrin quantification, adhesion and chemosensitivity assays with MEK1/2 inhibition","pmids":["22964375"],"confidence":"Medium","gaps":["KLK7-specific contribution not separable from KLK4/5/6 in the combined overexpression design","Mechanism linking protease activity to integrin loss not defined"]},{"year":2016,"claim":"Dissociating KLK7 protein level from secreted enzymatic activity in atopic dermatitis showed that impaired lamellar-granule secretion, not abundance, drives abnormal desquamation.","evidence":"Western blot, in situ zymography, EM and immunostaining of AD versus normal skin","pmids":["27769847"],"confidence":"High","gaps":["Cause of impaired secretion not identified","Correlative tissue analysis without genetic perturbation"]},{"year":2017,"claim":"Defining KLK7's chymotryptic cleavage specificity and establishing the S195A/D102N double mutant as the true catalytic-dead control set rigorous standards for downstream substrate profiling.","evidence":"MS-based PICS substrate profiling with single and double active-site mutants and kinetic assays","pmids":["28754951"],"confidence":"High","gaps":["Proteome-derived peptide libraries do not capture native folded substrates","No in vivo validation of preferred cleavage motifs"]},{"year":2017,"claim":"Adipose-specific KLK7 knockout revealed a metabolic and immunomodulatory role, linking the protease to high-fat-diet weight gain, insulin resistance, and pro-inflammatory macrophage polarization.","evidence":"Conditional adipose-specific Cre/lox knockout with metabolic phenotyping, cytokine quantification, and macrophage FACS","pmids":["28932870"],"confidence":"High","gaps":["Direct substrate in adipose tissue not identified","Mechanism connecting KLK7 to macrophage polarization unresolved"]},{"year":2019,"claim":"Secretome proteomics identified KLK7 substrates beyond the skin—pro-MMP10, IGFBP3/6 and thrombospondin 1—implicating it in ECM remodeling and migration in ovarian cancer.","evidence":"PROTOMAP/SILAC and TAILS proteomics in ovarian cancer secretomes with biochemical validation of select substrates","pmids":["30705123"],"confidence":"High","gaps":["Biological consequence of most identified cleavages not tested","Substrate processing demonstrated in cell secretome, not in vivo tumors"]},{"year":2020,"claim":"Mapping the IL-13/ERK1/2/EGR-1 axis to a defined promoter element explained how inflammatory signaling drives KLK7 expression in keratinocytes during atopic dermatitis.","evidence":"Promoter-luciferase reporter with EBS point mutation, EGR1 knockdown, and Egr1 knockout mice in an AD-like model","pmids":["33276948"],"confidence":"High","gaps":["Did not link transcriptional induction to quantitative changes in secreted protease activity","Other cytokine inputs to the promoter not surveyed"]},{"year":2022,"claim":"A KLK5-Fab crystal structure plus a KLK5/KLK7 bispecific antibody established allosteric, non-competitive inhibition and proved therapeutic compensation for LEKTI deficiency in vivo.","evidence":"Crystal structure of KLK5-Fab complex and antibody treatment in mouse Netherton syndrome and atopic dermatitis models","pmids":["36516271"],"confidence":"High","gaps":["Structural detail of the KLK7-specific inhibitory epitope less resolved than KLK5","Long-term consequences of dual protease blockade not assessed"]},{"year":2024,"claim":"Characterizing KLK7 autolysis and its cleavage of mast cell chymase and multiple interferons/interleukins broadened its role to active regulation of immune mediators.","evidence":"In vitro cleavage assays with inhibitors, active-site variants, recombinant chymase, and cytokines","pmids":["39655764"],"confidence":"Medium","gaps":["No in vivo confirmation that cytokine cleavage occurs physiologically","Single-lab in vitro reconstitution"]},{"year":2025,"claim":"Macrophage-specific knockout and human transcriptomics localized KLK7's adipose inflammatory role to macrophages, where it promotes migration and inflammatory activation.","evidence":"Macrophage-specific Cre/lox KO with flow cytometry, migration/adhesion assays, and human visceral adipose transcriptomics","pmids":["40154838"],"confidence":"High","gaps":["Direct macrophage substrate controlling adhesion/migration not identified","Causal relationship between human KLK7 expression and inflammation correlative only"]},{"year":2025,"claim":"Genetic epistasis in HPV-dependent cervical carcinogenesis placed KLK5/KLK7 upstream of a KLK14–PAR-2–RhoA/NF-κB pro-tumorigenic pathway.","evidence":"KLK5/KLK7 double knockout mice, RNA-seq, luciferase reporters, and human biopsy analysis","pmids":["40753921"],"confidence":"Medium","gaps":["KLK7-specific contribution not separated from KLK5","Mechanism of KLK14 activation by KLK7 not directly demonstrated"]},{"year":2025,"claim":"Astrocyte studies identified KLK7 as an NF-κB-repressed amyloid-β-degrading protease, extending its substrate repertoire to neurodegeneration-relevant targets.","evidence":"NF-κB inhibitor treatment of astrocytes and in vivo, Aβ degradation assays, and AD brain transcriptomic correlation (preprint)","pmids":["bio_10.1101_2025.03.02.641088"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed; single lab","Direct cleavage of Aβ by KLK7 not biochemically dissected"]},{"year":2026,"claim":"Structure-guided inhibitor development identified Thr190 in the S1 pocket as a selectivity determinant and validated functional blockade of KLK7-mediated chemokine cleavage in ovarian cancer.","evidence":"Medicinal chemistry from KLK7 crystal structure, Ki measurement, T190A mutagenesis, functional assays, and xenograft model","pmids":["41855304"],"confidence":"Medium","gaps":["Selectivity in vivo across the broader KLK family not fully established","Functional readouts focused on ovarian cancer context"]},{"year":null,"claim":"How KLK7's distinct context-specific substrate repertoires (skin desquamation, adipose/macrophage inflammation, cytokine and amyloid-β processing, cancer ECM remodeling) are coordinated and which cleavages are rate-limiting for each phenotype remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model linking transcriptional regulation, secretion, and inhibitor control across tissues","Physiological substrates outside skin largely defined in vitro","Direct KLK7-specific genetic dissection lacking in cancer epistasis studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,6,7]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,5,6,7]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,6,8]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,2,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,10,11]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[6,9]}],"complexes":[],"partners":["KLK5","LEKTI"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49862","full_name":"Kallikrein-7","aliases":["Serine protease 6","Stratum corneum chymotryptic enzyme","hSCCE"],"length_aa":253,"mass_kda":27.5,"function":"May catalyze the degradation of intercellular cohesive structures in the cornified layer of the skin in the continuous shedding of cells from the skin surface. Specific for amino acid residues with aromatic side chains in the P1 position. Cleaves insulin A chain at '14-Tyr-|-Gln-15' and insulin B chain at '6-Leu-|-Cys-7', '16-Tyr-|-Leu-17', '25-Phe-|-Tyr-26' and '26-Tyr-|-Thr-27'. Could play a role in the activation of precursors to inflammatory cytokines","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P49862/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLK7","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/KLK7","total_profiled":1310},"omim":[{"mim_id":"617471","title":"SERPIN PEPTIDASE INHIBITOR, CLADE A, MEMBER 12; SERPINA12","url":"https://www.omim.org/entry/617471"},{"mim_id":"615868","title":"SERINE PEPTIDASE INHIBITOR, KAZAL-TYPE, 6; SPINK6","url":"https://www.omim.org/entry/615868"},{"mim_id":"610627","title":"ALPHA-2-MACROGLOBULIN-LIKE 1; A2ML1","url":"https://www.omim.org/entry/610627"},{"mim_id":"610378","title":"GLIS FAMILY ZINC FINGER PROTEIN 1; GLIS1","url":"https://www.omim.org/entry/610378"},{"mim_id":"605644","title":"KALLIKREIN-RELATED PEPTIDASE 8; KLK8","url":"https://www.omim.org/entry/605644"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":90.8},{"tissue":"skin 1","ntpm":189.2}],"url":"https://www.proteinatlas.org/search/KLK7"},"hgnc":{"alias_symbol":["SCCE"],"prev_symbol":["PRSS6"]},"alphafold":{"accession":"P49862","domains":[{"cath_id":"2.40.10.10","chopping":"43-129_240-251","consensus_level":"medium","plddt":98.1694,"start":43,"end":251},{"cath_id":"2.40.10.10","chopping":"131-239","consensus_level":"medium","plddt":97.295,"start":131,"end":239}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49862","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49862-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49862-F1-predicted_aligned_error_v6.png","plddt_mean":91.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLK7","jax_strain_url":"https://www.jax.org/strain/search?query=KLK7"},"sequence":{"accession":"P49862","fasta_url":"https://rest.uniprot.org/uniprotkb/P49862.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49862/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49862"}},"corpus_meta":[{"pmid":"15140227","id":"PMC_15140227","title":"Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.","date":"2004","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15140227","citation_count":367,"is_preprint":false},{"pmid":"17596512","id":"PMC_17596512","title":"LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction.","date":"2007","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17596512","citation_count":237,"is_preprint":false},{"pmid":"15675955","id":"PMC_15675955","title":"LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum.","date":"2005","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15675955","citation_count":116,"is_preprint":false},{"pmid":"12738725","id":"PMC_12738725","title":"Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers.","date":"2003","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/12738725","citation_count":94,"is_preprint":false},{"pmid":"29319165","id":"PMC_29319165","title":"Long noncoding RNA NEAT1 regulate papillary thyroid cancer progression by modulating miR-129-5p/KLK7 expression.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29319165","citation_count":80,"is_preprint":false},{"pmid":"10974542","id":"PMC_10974542","title":"The KLK7 (PRSS6) gene, encoding for the stratum corneum chymotryptic enzyme is a new member of the human kallikrein gene family - genomic characterization, mapping, tissue expression and hormonal regulation.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10974542","citation_count":72,"is_preprint":false},{"pmid":"18774391","id":"PMC_18774391","title":"Analysis of the individual and aggregate genetic contributions of previously identified serine peptidase inhibitor Kazal type 5 (SPINK5), kallikrein-related peptidase 7 (KLK7), and filaggrin (FLG) polymorphisms to eczema risk.","date":"2008","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18774391","citation_count":56,"is_preprint":false},{"pmid":"36516271","id":"PMC_36516271","title":"Dual antibody inhibition of KLK5 and KLK7 for Netherton syndrome and atopic dermatitis.","date":"2022","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36516271","citation_count":45,"is_preprint":false},{"pmid":"15766562","id":"PMC_15766562","title":"KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15766562","citation_count":44,"is_preprint":false},{"pmid":"19350120","id":"PMC_19350120","title":"Clinical significance of kallikrein-related peptidase 7 (KLK7) in colorectal cancer.","date":"2009","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/19350120","citation_count":39,"is_preprint":false},{"pmid":"22964375","id":"PMC_22964375","title":"Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance.","date":"2012","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22964375","citation_count":38,"is_preprint":false},{"pmid":"30456805","id":"PMC_30456805","title":"LncRNA FOXD2-AS1 accelerates the papillary thyroid cancer progression through regulating the miR-485-5p/KLK7 axis.","date":"2018","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30456805","citation_count":37,"is_preprint":false},{"pmid":"27769847","id":"PMC_27769847","title":"Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis.","date":"2016","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27769847","citation_count":36,"is_preprint":false},{"pmid":"25477184","id":"PMC_25477184","title":"Kallikrein family proteases KLK6 and KLK7 are potential early detection and diagnostic biomarkers for serous and papillary serous ovarian cancer subtypes.","date":"2014","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/25477184","citation_count":35,"is_preprint":false},{"pmid":"11906548","id":"PMC_11906548","title":"Expression of the protease inhibitor antileukoprotease and the serine protease stratum corneum chymotryptic enzyme (SCCE) is coordinated in ovarian tumors.","date":"2001","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/11906548","citation_count":32,"is_preprint":false},{"pmid":"25153388","id":"PMC_25153388","title":"Kallikrein-related peptidase 7 (KLK7) is a proliferative factor that is aberrantly expressed in human colon cancer.","date":"2014","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25153388","citation_count":32,"is_preprint":false},{"pmid":"28932870","id":"PMC_28932870","title":"Ablation of kallikrein 7 (KLK7) in adipose tissue ameliorates metabolic consequences of high fat diet-induced obesity by counteracting adipose tissue inflammation in vivo.","date":"2017","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/28932870","citation_count":32,"is_preprint":false},{"pmid":"15492784","id":"PMC_15492784","title":"Expression of human kallikrein 7 (hK7/SCCE) and its inhibitor antileukoprotease (ALP/SLPI) in uterine endocervical glands and in cervical adenocarcinomas.","date":"2004","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/15492784","citation_count":30,"is_preprint":false},{"pmid":"31270675","id":"PMC_31270675","title":"MicroRNA-326 Inhibits Apoptosis and Promotes Proliferation of Dopaminergic Neurons in Parkinson's Disease Through Suppression of KLK7-Mediated MAPK Signaling Pathway.","date":"2019","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/31270675","citation_count":30,"is_preprint":false},{"pmid":"30705123","id":"PMC_30705123","title":"Integration of Two In-depth Quantitative Proteomics Approaches Determines the Kallikrein-related Peptidase 7 (KLK7) Degradome in Ovarian Cancer Cell Secretome.","date":"2019","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/30705123","citation_count":21,"is_preprint":false},{"pmid":"18163887","id":"PMC_18163887","title":"Tissue-specific promoter utilisation of the kallikrein-related peptidase genes, KLK5 and KLK7, and cellular localisation of the encoded proteins suggest roles in exocrine pancreatic function.","date":"2008","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18163887","citation_count":18,"is_preprint":false},{"pmid":"33276948","id":"PMC_33276948","title":"EGR-1 acts as a transcriptional activator of KLK7 under IL-13 stimulation.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/33276948","citation_count":13,"is_preprint":false},{"pmid":"34308939","id":"PMC_34308939","title":"Generation of a quenched phosphonate activity-based probe for labelling the active KLK7 protease.","date":"2021","source":"Organic & biomolecular chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34308939","citation_count":11,"is_preprint":false},{"pmid":"40154838","id":"PMC_40154838","title":"The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.","date":"2025","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/40154838","citation_count":7,"is_preprint":false},{"pmid":"38961454","id":"PMC_38961454","title":"KLK7 expression in human tumors: a tissue microarray study on 13,447 tumors.","date":"2024","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38961454","citation_count":7,"is_preprint":false},{"pmid":"37353723","id":"PMC_37353723","title":"Mini-PBPK-Based Population Model and Covariate Analysis to Assess the Complex Pharmacokinetics and Pharmacodynamics of RO7449135, an Anti-KLK5/KLK7 Bispecific Antibody in Cynomolgus Monkeys.","date":"2023","source":"The AAPS journal","url":"https://pubmed.ncbi.nlm.nih.gov/37353723","citation_count":7,"is_preprint":false},{"pmid":"37672660","id":"PMC_37672660","title":"Retrospective pharmacogenetic study of psoriasis highlights the role of KLK7 in tumour necrosis factor signalling.","date":"2023","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/37672660","citation_count":7,"is_preprint":false},{"pmid":"28754951","id":"PMC_28754951","title":"Mass spectrometry-based determination of Kallikrein-related peptidase 7 (KLK7) cleavage preferences and subsite dependency.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28754951","citation_count":7,"is_preprint":false},{"pmid":"31006337","id":"PMC_31006337","title":"Molecular characteristics and association analysis with litter size trait for porcine KLK7 gene.","date":"2019","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/31006337","citation_count":4,"is_preprint":false},{"pmid":"27262076","id":"PMC_27262076","title":"Experiment research of cisplatin implants inhibiting transplantation tumor growth and regulating the expression of KLK7 and E-cad of tumor-bearing mice with gastric cancer.","date":"2016","source":"Asian Pacific journal of tropical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27262076","citation_count":4,"is_preprint":false},{"pmid":"38189409","id":"PMC_38189409","title":"Increase of KLK7, cytokeratin 5/6, and elafin expression in head and neck squamous cell carcinoma compared with lung squamous cell carcinoma.","date":"2024","source":"Journal of histotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/38189409","citation_count":3,"is_preprint":false},{"pmid":"39991575","id":"PMC_39991575","title":"KLK7 Involvement in Thyroid Papillary Carcinoma Cell Migration and Invasion by EMT via MAPK/ERK Pathways.","date":"2025","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39991575","citation_count":3,"is_preprint":false},{"pmid":"39655764","id":"PMC_39655764","title":"Analysis of kallikrein-related peptidase 7 (KLK7) autolysis reveals novel protease and cytokine substrates.","date":"2024","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39655764","citation_count":3,"is_preprint":false},{"pmid":"29779317","id":"PMC_29779317","title":"[The expression of KLK7 in pancreatic cancer and the effects on the biological behavior of pancreatic cancer cells].","date":"2018","source":"Zhonghua wai ke za zhi [Chinese journal of surgery]","url":"https://pubmed.ncbi.nlm.nih.gov/29779317","citation_count":2,"is_preprint":false},{"pmid":"40753921","id":"PMC_40753921","title":"KLK5 and KLK7 drive cervical carcinoma via KLK14-dependent RhoA and NF-κB pathways.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40753921","citation_count":1,"is_preprint":false},{"pmid":"41335524","id":"PMC_41335524","title":"KLK7 overexpression promotes an aggressive phenotype and facilitates peritoneal dissemination in colorectal cancer cells.","date":"2025","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/41335524","citation_count":1,"is_preprint":false},{"pmid":"39871127","id":"PMC_39871127","title":"Significance of KLK7 expression, polymorphisms, and function in sheep horn growth.","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/39871127","citation_count":0,"is_preprint":false},{"pmid":"41855304","id":"PMC_41855304","title":"Development of kallikrein-related peptidase 7 (KLK7) inhibitors and use in a species-adapted model for ovarian cancer.","date":"2026","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41855304","citation_count":0,"is_preprint":false},{"pmid":"41053179","id":"PMC_41053179","title":"Detection of probable phytochemical inhibitors targeting kallikrein related peptidase 7 (KLK7) in ovarian cancer through molecular dynamics and virtual screening approaches.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41053179","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.02.641088","title":"Inhibition of NF-κB signaling pathway in astrocytes facilitates amyloid-β clearance by kallikrein-related peptidase 7","date":"2025-03-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.02.641088","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.14.681588","title":"Impaired store-operated Ca  <sup>2+</sup>  entry in mouse epidermis leads to reduced epidermal barrier function via Klk activation","date":"2025-10-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.14.681588","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23953,"output_tokens":4789,"usd":0.071847,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12886,"output_tokens":4863,"usd":0.093003,"stage2_stop_reason":"end_turn"},"total_usd":0.16485,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"KLK7 (SCCE) directly cleaves corneodesmosin (CDSN) and desmocollin 1 (DSC1) at acidic pH, but is unable to degrade desmoglein 1 (DSG1). Oligosaccharide residues on CDSN do not protect it against KLK7 proteolysis. KLK5 (SCTE) can activate the proform of KLK7, suggesting a protease cascade in desquamation.\",\n      \"method\": \"In vitro protease activity assay with recombinant and epidermal protein substrates; enzymatic deglycosylation experiments; proenzyme activation assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution of substrate cleavage with multiple substrates and glycosylation controls, replicated across two proteases\",\n      \"pmids\": [\"15140227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LEKTI fragments specifically inhibit KLK7 (as well as KLK5 and KLK14) in a pH-dependent manner; at acidic pH, active KLK5 is released from the LEKTI complex, allowing corneodesmosomal cleavage in superficial stratum corneum layers. The pH gradient of the epidermis thus governs the spatial regulation of KLK7 activity.\",\n      \"method\": \"Biochemical inhibition kinetics assays; pH-dependent binding/release experiments; analysis of LEKTI fragments generated by furin cleavage in cultured keratinocytes and epidermis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted inhibitor-protease kinetics with multiple LEKTI domain fragments, pH-dependent release demonstrated in vitro with functional validation\",\n      \"pmids\": [\"17596512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In normal human epidermis, KLK7 and KLK5 are co-localized in lamellar granules but are spatially separated from LEKTI, which is packaged earlier. KLK7 secretion from lamellar granules into the extracellular space precedes that of the inhibitor, establishing a temporally regulated proteolytic system for desquamation.\",\n      \"method\": \"Confocal laser scanning microscopy and immunoelectron microscopy of normal and Netherton syndrome skin\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal immunolocalization with two orthogonal imaging methods (confocal + immunoelectron microscopy) in both normal and disease tissue\",\n      \"pmids\": [\"15675955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In atopic dermatitis lesions, KLK7 secretion from lamellar granules is impaired despite elevated KLK7 protein levels; in situ zymography shows no significant elevation of KLK7 enzymatic activity at the corneocyte surface, and LEKTI expression is upregulated. This imbalance leads to abnormal corneodesmosin degradation patterns and compact hyperkeratosis.\",\n      \"method\": \"Western blot, in situ zymography of tape-stripped corneocytes, electron microscopy, immunostaining of AD and normal skin\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (zymography, western blot, EM, immunostaining) in a single lab establishing mechanistic dissociation between protein level and secreted enzymatic activity\",\n      \"pmids\": [\"27769847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inhibitory antibodies against KLK5 and KLK7, combined as a bispecific antibody (RO7449135), compensate for LEKTI deficiency in mouse models of Netherton syndrome and atopic dermatitis, restoring skin barrier integrity and reducing inflammation. A crystal structure of KLK5 with the inhibitory Fab revealed allosteric inhibition distal to the active site, establishing a non-competitive inhibitory mechanism.\",\n      \"method\": \"Crystal structure determination of KLK5-Fab complex; mouse models of NS and AD with antibody treatment; skin barrier function and inflammation assays\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation in multiple in vivo disease models, bispecific antibody engineering with mechanistic structural insight\",\n      \"pmids\": [\"36516271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLK7 exhibits chymotryptic-like cleavage preferences with a preference for hydrophobic residues at P2-P1 (non-prime) and hydrophilic residues at P1'-P2' (prime) subsites. Single active-site mutant KLK7 (S195A) retains residual catalytic activity, but the double mutant (S195A + D102N) achieves catalytic inactivity, establishing that standard single-mutant controls are insufficient for MS-based studies.\",\n      \"method\": \"Mass spectrometry-based PICS (Proteomic Identification of protease Cleavage Sites) with human proteome-derived peptide libraries; active-site mutagenesis (S195A single and S195A/D102N double mutants); kinetic assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and MS-based substrate profiling in a single rigorous study\",\n      \"pmids\": [\"28754951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In the secretome of ovarian cancer cells (SKOV-3 and OVMZ-6), KLK7 directly activates pro-MMP10, cleaves IGFBP3 and IGFBP6, and cleaves thrombospondin 1 generating a potentially bioactive N-terminal fragment. Sixteen additional novel putative substrates were identified, enriched for cell adhesion, extracellular matrix remodeling, and cell migration functions.\",\n      \"method\": \"Quantitative proteomics (PROTOMAP + SILAC) and Terminal Amine Isotopic Labeling of Substrates (TAILS) in ovarian cancer cell secretomes; biochemical validation of specific substrates\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two technically orthogonal proteomics approaches plus biochemical validation of select substrates in a single rigorous study\",\n      \"pmids\": [\"30705123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"KLK7 undergoes autolysis at two sites in the 170 and 99 loops (chymotrypsinogen numbering), resulting in loss of enzymatic activity. KLK7 cleaves mast cell chymase, resulting in loss of chymase activity. KLK7 also hydrolyzes multiple cytokines including IFN-α, IFN-β, IFN-γ, IL-28A/IFN-λ2, IL-20, IL-22, and IL-27.\",\n      \"method\": \"Protease-specific inhibitor assays; active-site variant analysis; in vitro cleavage assays with recombinant chymase and cytokines; activity measurements\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution with inhibitors and variants, single lab, novel substrates but no in vivo validation\",\n      \"pmids\": [\"39655764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KLK7 encodes a secreted chymotrypsin-like serine protease. Its expression is up-regulated by estrogens and glucocorticoids in the breast carcinoma cell line BT-474, identifying hormonal regulation of KLK7 expression.\",\n      \"method\": \"Northern blot; hormone treatment of BT-474 cells; genomic characterization and phylogenetic analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct hormonal induction measured by Northern blot in a single cell line, single lab\",\n      \"pmids\": [\"10974542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Combined stable overexpression of KLK4, KLK5, KLK6, and KLK7 in ovarian cancer cells (OV-MZ-6) downregulates α5β1 and αvβ3 integrin expression, reduces adhesion to vitronectin and fibronectin, and increases resistance to paclitaxel (but not carboplatin). Paclitaxel resistance was not blocked by the MEK1/2 inhibitor U0126, indicating MAPK-independent mechanisms.\",\n      \"method\": \"Stable transfection with KLK expression plasmids; integrin quantification; adhesion assays; chemosensitivity assays; MEK1/2 inhibitor treatment; confocal microscopy\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple assays in a single lab but note: this is a combined KLK4-7 overexpression study, not KLK7 alone, limiting specificity of attribution\",\n      \"pmids\": [\"22964375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adipose tissue-specific knockout of KLK7 (ATKlk7−/−) in mice on high-fat diet results in less weight gain, preferential subcutaneous fat expansion, improved whole-body insulin sensitivity, higher energy expenditure, reduced pro-inflammatory cytokine expression, and increased anti-inflammatory M2 macrophage polarization in epididymal adipose tissue. These effects are associated with altered adipokine secretion including lower leptin.\",\n      \"method\": \"Conditional adipose-specific gene targeting (Cre/lox); metabolic phenotyping; cytokine quantification; macrophage FACS analysis; adipokine measurement\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with multiple orthogonal metabolic and immunological readouts, clear loss-of-function phenotype\",\n      \"pmids\": [\"28932870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Macrophage-specific KLK7 knockout (KLK7MKO) in high-fat diet mice reduces systemic inflammation, decreases inflammatory macrophage infiltration and activation in epididymal adipose tissue, reduces pro-inflammatory gene expression in macrophages, and restricts macrophage migration by increasing cell adhesion. In human visceral adipose tissue (n=1143), KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression.\",\n      \"method\": \"Macrophage-specific Cre/lox KO; flow cytometry; gene expression analysis; migration/adhesion assays; human transcriptomic data analysis\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KO with multiple orthogonal functional readouts plus human transcriptomic validation\",\n      \"pmids\": [\"40154838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-13 stimulation induces KLK7 transcription in keratinocytes via the ERK1/2 MAPK pathway activating the transcription factor EGR-1, which directly binds an EGR-1 binding sequence (EBS) in the KLK7 promoter. Point mutation of the EBS abrogates IL-13-induced KLK7 promoter activity; EGR1 knockdown abolishes KLK7 induction; and Egr1 knockout mice show reduced KLK7 expression in atopic dermatitis-like lesions.\",\n      \"method\": \"Promoter-luciferase reporter assay with point mutation of EBS; ChIP or direct binding assay for EGR-1 to EBS; shRNA knockdown of EGR1; Egr1 knockout mice with AD-like model; ERK1/2 inhibitor treatment\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with mutagenesis, KD, and KO all converging on the same IL13-ERK-EGR1-KLK7 axis in a single study\",\n      \"pmids\": [\"33276948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK5 and KLK7 drive HPV-dependent cervical carcinogenesis; absence of both KLK5 and KLK7 ameliorates the HPV-dependent phenotype. The mechanism operates via KLK14 activation, with KLK14 exerting pro-tumorigenic effects through PAR-2-dependent RhoA and NF-κB signaling pathways.\",\n      \"method\": \"Genetically engineered mice (KLK5/KLK7 double knockout); bulk RNA-seq; luciferase reporter assays; human biopsy analysis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis in mouse model with reporter assay establishes pathway position, but KLK7-specific contribution is not separated from KLK5 in the mechanistic studies\",\n      \"pmids\": [\"40753921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NF-κB signaling in astrocytes negatively regulates KLK7 mRNA expression; inhibition of NF-κB increases KLK7 expression and promotes amyloid-β (Aβ) degradation in astrocytes. In vivo, NF-κB inhibitor injection upregulates Klk7 expression and reduces Aβ levels, identifying KLK7 as an astrocyte-derived Aβ-degrading protease regulated by NMDA receptor-NF-κB signaling.\",\n      \"method\": \"NF-κB inhibitor treatment of astrocytes; KLK7 expression measurement; Aβ degradation assay; in vivo NF-κB inhibitor injection in mouse model; correlation analysis of NF-κB family and KLK7 in AD brain transcriptomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint with in vitro and in vivo functional validation but single lab, not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.02.641088\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Impaired store-operated Ca2+ entry (SOCE) via STIM1/2 knockout in mouse keratinocytes leads to elevated Klk7 levels and increased chymotrypsin-like serine protease activity at the epidermal surface, causing hyperkeratosis and impaired barrier function. Desmoglein 1 alterations are associated with excess KLK7 activity in this context.\",\n      \"method\": \"Epithelial-specific Stim1/2 double knockout mice; RNA-seq; in situ serine protease activity measurement; TEWL measurement; histology\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, KLK7 activation is a downstream consequence of SOCE loss rather than direct mechanistic study of KLK7 itself; indirect evidence\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.681588\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Structure-guided development of KLK7 inhibitors using a published crystal structure identified the S1 binding pocket, where threonine 190 is a key selectivity determinant (vs. murine Klk7 which has threonine 190). Mutation T190A in murine Klk7 restores inhibitor sensitivity. Inhibitors block KLK7-mediated chemokine cleavage and moesin gene upregulation in ovarian cancer cells.\",\n      \"method\": \"Medicinal chemistry guided by published KLK7 crystal structure; Ki measurement; site-directed mutagenesis of T190A; functional assays (chemokine cleavage, moesin expression); xenograft mouse model\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structure-guided inhibitor design with mutagenesis confirming active site residue, functional validation in cells and in vivo, single lab\",\n      \"pmids\": [\"41855304\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLK7 is a secreted chymotrypsin-like serine protease that cleaves corneodesmosomal proteins (corneodesmosin, desmocollin 1) to drive epidermal desquamation; its activity is activated by KLK5 (via proenzyme cleavage), spatially and temporally controlled by the LEKTI inhibitor through a pH-dependent interaction in lamellar granules, transcriptionally regulated by the IL-13/ERK/EGR-1 axis in keratinocytes, and exerts additional roles in adipose tissue inflammation (controlling macrophage polarization and migration), amyloid-β clearance in astrocytes (negatively regulated by NF-κB), and cancer progression (via ECM remodeling, integrin downregulation, cytokine cleavage, and downstream activation of KLK14-PAR-2-RhoA/NF-κB signaling).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KLK7 is a secreted chymotrypsin-like serine protease that drives epidermal desquamation by directly cleaving the corneodesmosomal proteins corneodesmosin (CDSN) and desmocollin 1 (DSC1) at acidic pH, while sparing desmoglein 1 [#0]. Its catalysis follows a chymotryptic specificity, favoring hydrophobic residues at the non-prime subsites, and depends on the canonical Ser195/Asp102 catalytic dyad [#5]. KLK7 operates within a tightly regulated proteolytic system: its proform is activated by KLK5 [#0], and its activity is spatially and temporally constrained by the LEKTI inhibitor through a pH-dependent interaction, with KLK7 secreted from lamellar granules ahead of LEKTI and active enzyme released as the stratum corneum acidifies [#1, #2]. Disruption of this balance underlies barrier disease: impaired KLK7 secretion produces abnormal corneodesmosin degradation and compact hyperkeratosis in atopic dermatitis [#3], and combined antibody inhibition of KLK5 and KLK7 compensates for LEKTI deficiency to restore the barrier in Netherton syndrome and atopic dermatitis models [#4]. KLK7 transcription in keratinocytes is induced by IL-13 through an ERK1/2–EGR-1 axis acting on an EGR-1 binding site in the KLK7 promoter [#12]. Beyond the skin, KLK7 cleaves a broad set of extracellular substrates—activating pro-MMP10, processing IGFBP3/6 and thrombospondin 1 in ovarian cancer secretomes [#6], and hydrolyzing multiple cytokines and mast cell chymase [#7]—and contributes to adipose tissue inflammation, where tissue- and macrophage-specific knockout reduces inflammatory macrophage activation, restricts macrophage migration by promoting adhesion, and improves metabolic outcomes [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing KLK7 as a secreted chymotrypsin-like serine protease and showing its expression is hormonally controlled framed it as a regulated, potentially disease-relevant enzyme.\",\n      \"evidence\": \"Northern blot and hormone treatment of BT-474 breast carcinoma cells with genomic characterization\",\n      \"pmids\": [\"10974542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physiological substrate identified at this stage\", \"Hormonal induction shown in a single cancer cell line only\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identifying corneodesmosin and desmocollin 1 as direct substrates, and KLK5 as the activator of pro-KLK7, defined KLK7's role in a desquamation protease cascade.\",\n      \"evidence\": \"In vitro protease assays with recombinant and epidermal substrates, deglycosylation controls, and proenzyme activation assay\",\n      \"pmids\": [\"15140227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro cleavage does not establish in vivo rate-limiting roles\", \"Did not address how activity is spatially confined in tissue\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing that KLK7/KLK5 and LEKTI are differentially packaged and secreted from lamellar granules explained how proteolysis is temporally gated during corneocyte maturation.\",\n      \"evidence\": \"Confocal and immunoelectron microscopy of normal and Netherton syndrome skin\",\n      \"pmids\": [\"15675955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical trigger for inhibitor release\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating pH-dependent LEKTI inhibition of KLK7 connected the epidermal pH gradient to the spatial activation of desquamatory proteolysis in superficial layers.\",\n      \"evidence\": \"Inhibition kinetics and pH-dependent binding/release assays with LEKTI fragments from keratinocytes\",\n      \"pmids\": [\"17596512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of pH gradient in intact tissue not measured\", \"Did not separate KLK7 from KLK5/KLK14 contributions to desquamation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Combined KLK4-7 overexpression in ovarian cancer cells linked these proteases to integrin downregulation, reduced ECM adhesion, and chemoresistance, suggesting a tumor-modifying role.\",\n      \"evidence\": \"Stable transfection, integrin quantification, adhesion and chemosensitivity assays with MEK1/2 inhibition\",\n      \"pmids\": [\"22964375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KLK7-specific contribution not separable from KLK4/5/6 in the combined overexpression design\", \"Mechanism linking protease activity to integrin loss not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissociating KLK7 protein level from secreted enzymatic activity in atopic dermatitis showed that impaired lamellar-granule secretion, not abundance, drives abnormal desquamation.\",\n      \"evidence\": \"Western blot, in situ zymography, EM and immunostaining of AD versus normal skin\",\n      \"pmids\": [\"27769847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cause of impaired secretion not identified\", \"Correlative tissue analysis without genetic perturbation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining KLK7's chymotryptic cleavage specificity and establishing the S195A/D102N double mutant as the true catalytic-dead control set rigorous standards for downstream substrate profiling.\",\n      \"evidence\": \"MS-based PICS substrate profiling with single and double active-site mutants and kinetic assays\",\n      \"pmids\": [\"28754951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proteome-derived peptide libraries do not capture native folded substrates\", \"No in vivo validation of preferred cleavage motifs\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Adipose-specific KLK7 knockout revealed a metabolic and immunomodulatory role, linking the protease to high-fat-diet weight gain, insulin resistance, and pro-inflammatory macrophage polarization.\",\n      \"evidence\": \"Conditional adipose-specific Cre/lox knockout with metabolic phenotyping, cytokine quantification, and macrophage FACS\",\n      \"pmids\": [\"28932870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate in adipose tissue not identified\", \"Mechanism connecting KLK7 to macrophage polarization unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Secretome proteomics identified KLK7 substrates beyond the skin—pro-MMP10, IGFBP3/6 and thrombospondin 1—implicating it in ECM remodeling and migration in ovarian cancer.\",\n      \"evidence\": \"PROTOMAP/SILAC and TAILS proteomics in ovarian cancer secretomes with biochemical validation of select substrates\",\n      \"pmids\": [\"30705123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biological consequence of most identified cleavages not tested\", \"Substrate processing demonstrated in cell secretome, not in vivo tumors\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapping the IL-13/ERK1/2/EGR-1 axis to a defined promoter element explained how inflammatory signaling drives KLK7 expression in keratinocytes during atopic dermatitis.\",\n      \"evidence\": \"Promoter-luciferase reporter with EBS point mutation, EGR1 knockdown, and Egr1 knockout mice in an AD-like model\",\n      \"pmids\": [\"33276948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link transcriptional induction to quantitative changes in secreted protease activity\", \"Other cytokine inputs to the promoter not surveyed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A KLK5-Fab crystal structure plus a KLK5/KLK7 bispecific antibody established allosteric, non-competitive inhibition and proved therapeutic compensation for LEKTI deficiency in vivo.\",\n      \"evidence\": \"Crystal structure of KLK5-Fab complex and antibody treatment in mouse Netherton syndrome and atopic dermatitis models\",\n      \"pmids\": [\"36516271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the KLK7-specific inhibitory epitope less resolved than KLK5\", \"Long-term consequences of dual protease blockade not assessed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Characterizing KLK7 autolysis and its cleavage of mast cell chymase and multiple interferons/interleukins broadened its role to active regulation of immune mediators.\",\n      \"evidence\": \"In vitro cleavage assays with inhibitors, active-site variants, recombinant chymase, and cytokines\",\n      \"pmids\": [\"39655764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo confirmation that cytokine cleavage occurs physiologically\", \"Single-lab in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Macrophage-specific knockout and human transcriptomics localized KLK7's adipose inflammatory role to macrophages, where it promotes migration and inflammatory activation.\",\n      \"evidence\": \"Macrophage-specific Cre/lox KO with flow cytometry, migration/adhesion assays, and human visceral adipose transcriptomics\",\n      \"pmids\": [\"40154838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct macrophage substrate controlling adhesion/migration not identified\", \"Causal relationship between human KLK7 expression and inflammation correlative only\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetic epistasis in HPV-dependent cervical carcinogenesis placed KLK5/KLK7 upstream of a KLK14–PAR-2–RhoA/NF-κB pro-tumorigenic pathway.\",\n      \"evidence\": \"KLK5/KLK7 double knockout mice, RNA-seq, luciferase reporters, and human biopsy analysis\",\n      \"pmids\": [\"40753921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"KLK7-specific contribution not separated from KLK5\", \"Mechanism of KLK14 activation by KLK7 not directly demonstrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Astrocyte studies identified KLK7 as an NF-κB-repressed amyloid-β-degrading protease, extending its substrate repertoire to neurodegeneration-relevant targets.\",\n      \"evidence\": \"NF-κB inhibitor treatment of astrocytes and in vivo, Aβ degradation assays, and AD brain transcriptomic correlation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.03.02.641088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed; single lab\", \"Direct cleavage of Aβ by KLK7 not biochemically dissected\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Structure-guided inhibitor development identified Thr190 in the S1 pocket as a selectivity determinant and validated functional blockade of KLK7-mediated chemokine cleavage in ovarian cancer.\",\n      \"evidence\": \"Medicinal chemistry from KLK7 crystal structure, Ki measurement, T190A mutagenesis, functional assays, and xenograft model\",\n      \"pmids\": [\"41855304\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity in vivo across the broader KLK family not fully established\", \"Functional readouts focused on ovarian cancer context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KLK7's distinct context-specific substrate repertoires (skin desquamation, adipose/macrophage inflammation, cytokine and amyloid-β processing, cancer ECM remodeling) are coordinated and which cleavages are rate-limiting for each phenotype remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model linking transcriptional regulation, secretion, and inhibitor control across tissues\", \"Physiological substrates outside skin largely defined in vitro\", \"Direct KLK7-specific genetic dissection lacking in cancer epistasis studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 6, 7]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 5, 6, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 6, 8]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 10, 11]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KLK5\", \"LEKTI\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}