{"gene":"KLK7","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":1996,"finding":"KLK7 (SCCE/hK7) was identified as a chymotrypsin-like serine protease expressed in the stratum corneum, responsible for the cell shedding (desquamation) process; the gene was localized to chromosome 19q13.3.","method":"cDNA cloning, sequence homology analysis, differential display","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — original cloning with sequence characterization; single lab foundational discovery","pmids":["8898378"],"is_preprint":false},{"year":2000,"finding":"KLK7 encodes a secreted chymotryptic serine protease (SCCE/hK7) whose expression is upregulated by estrogens and glucocorticoids in breast carcinoma cells (BT-474), and is expressed in brain, kidney, mammary and salivary glands in addition to skin; the gene maps to 19q13.3-q13.4 between KLK6 and KLK8.","method":"RT-PCR, Northern blot, genomic organization analysis, hormonal stimulation assays in BT-474 cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — direct hormonal regulation demonstrated in cell-based assay; single lab","pmids":["10974542"],"is_preprint":false},{"year":2001,"finding":"Antileukoprotease (ALP/SLPI) is co-expressed with KLK7 (SCCE) in ovarian tumors and has been identified as a specific inhibitor of KLK7 enzymatic activity.","method":"Northern blot, semi-quantitative PCR, immunohistochemistry; correlation of SCCE and ALP expression","journal":"International journal of gynecological cancer","confidence":"Low","confidence_rationale":"Tier 3 — inhibitor relationship inferred from co-expression; direct Ki measurement not reported in this paper","pmids":["11906548"],"is_preprint":false},{"year":2004,"finding":"KLK7 (SCCE/hK7) directly cleaves the corneodesmosomal proteins corneodesmosin (CDSN) and desmocollin 1 (DSC1) at acidic pH (mimicking stratum corneum pH), but cannot degrade desmoglein 1 (DSG1) alone; KLK5 (SCTE) activates the proform of KLK7 (pro-SCCE) and enables degradation of all three corneodesmosomal components including DSG1. Oligosaccharide residues on CDSN do not protect it from KLK7 proteolysis.","method":"In vitro protease cleavage assays with recombinant and epidermal forms of substrates at acidic pH; enzymatic deglycosylation experiments; SDS-PAGE analysis of cleavage products","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro cleavage assays with defined substrates and proform activation, replicated with multiple substrate forms","pmids":["15140227"],"is_preprint":false},{"year":2005,"finding":"KLK7 is localized to lamellar granules in the stratum granulosum separately from LEKTI, with LEKTI secreted earlier than KLK7 and KLK5; this spatial and temporal separation ensures LEKTI is present extracellularly before KLK7 is released, preventing premature desquamation. In Netherton syndrome skin lacking LEKTI, an abnormal split appears in the superficial stratum granulosum.","method":"Confocal laser scanning microscopy and immunoelectron microscopy of normal and Netherton syndrome skin biopsies","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 — dual-modality direct localization with functional consequence demonstrated in disease skin; replicated across normal and NS cases","pmids":["15675955"],"is_preprint":false},{"year":2006,"finding":"Multiple KLK family members including KLK7 participate in desquamation through cleavage of desmoglein 1 (within cadherin repeats, Ca2+-binding sites, and juxtamembrane region) and are regulated by LEKTI fragments; KLK7 digests the ectodomain of desmoglein 1 in vitro. KLK7 was not significantly inhibited by secretory leukocyte protease inhibitor (SLPI) or elafin in contrast to earlier reports.","method":"In vitro protease digestion assays with recombinant desmoglein 1 ectodomain; Ki measurements with recombinant LEKTI fragments; SDS-PAGE","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro cleavage and inhibition kinetics with defined recombinant proteins","pmids":["17158887"],"is_preprint":false},{"year":2007,"finding":"LEKTI is processed by furin into multiple single- and multi-domain fragments (D1, D5, D6, D8-D11, D9-D15); these fragments specifically and differentially inhibit KLK5, KLK7, and KLK14 but not other serine proteases tested. The KLK5-LEKTI(D8-D11) interaction is rapid, tight, and functionally irreversible; crucially, acidic pH (as found in the superficial stratum corneum) causes release of active KLK5 from the inhibitory complex, providing a pH-dependent gating mechanism for KLK-mediated corneodesmosomal cleavage.","method":"Biochemical inhibition kinetics; furin cleavage assays; pH-dependent binding/release assays; functional protease activity assays on KLK5, KLK7, KLK14","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with kinetic analysis and pH-dependent mechanistic dissection; replicated across multiple LEKTI fragments","pmids":["17596512"],"is_preprint":false},{"year":2008,"finding":"KLK5 and KLK7 generate tissue-specific (pancreas) transcripts driven by alternative promoters distinct from those used in skin or ovary; immunohistochemistry localizes both enzymes predominantly to acinar cells of the exocrine pancreas, suggesting roles in digestion.","method":"Northern blot of 19 normal human tissues; in silico promoter analysis; immunohistochemistry; RT-PCR","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization by IHC and molecular characterization of alternative transcripts; single lab, no functional reconstitution","pmids":["18163887"],"is_preprint":false},{"year":2012,"finding":"Combined overexpression of KLK4, KLK5, KLK6, and KLK7 in ovarian cancer cells (OV-MZ-6) downregulates α5β1 and αvβ3 integrin expression, reduces cell adhesion to vitronectin and fibronectin, and confers paclitaxel resistance (not carboplatin resistance) through reduced apoptotic stimuli; this resistance is independent of MEK1/2 signaling.","method":"Stable transfection; quantitative gene and protein expression; confocal microscopy; cell adhesion assays; chemosensitivity assays; MEK inhibitor (U0126) epistasis","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with genetic epistasis; combined KLK overexpression limits attribution specifically to KLK7","pmids":["22964375"],"is_preprint":false},{"year":2014,"finding":"KLK7 overexpression in HT29 colon cancer cells increases cell proliferation in vitro and tumor growth in vivo; KLK7 protein is aberrantly expressed and secreted in colon cancer tissues and cell lines but absent in normal colonic epithelium.","method":"Stable transfection with KLK7 expression plasmid; CCK-8 proliferation assay; subcutaneous xenograft in nude mice; Ki-67 staining; Western blot; immunofluorescence","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function with defined proliferative phenotype both in vitro and in vivo; single lab","pmids":["25153388"],"is_preprint":false},{"year":2016,"finding":"In atopic dermatitis lesional skin, KLK7 secretion from lamellar granules is impaired despite increased total KLK7 protein levels, resulting in ineffective KLK activation and abnormal corneodesmosin degradation; concurrently, LEKTI expression is upregulated as a compensatory mechanism to prevent further barrier dysfunction.","method":"Western blot analysis of stratum corneum; in situ zymography on tape-stripped corneocytes; immunostaining; electron microscopy of lamellar granules","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods demonstrating impaired secretion with functional consequence; single lab","pmids":["27769847"],"is_preprint":false},{"year":2017,"finding":"Adipose tissue-specific Klk7 knockout mice (ATKlk7-/-) show less weight gain, preferential subcutaneous adipose expansion, improved insulin sensitivity, higher energy expenditure, reduced pro-inflammatory cytokine expression, and increased anti-inflammatory M2 macrophages in epididymal adipose tissue under high-fat diet. KLK7 deficiency alters adipokine secretion including reduced circulating leptin.","method":"Conditional gene targeting (Cre-lox) in adipose tissue; metabolic phenotyping (glucose tolerance, insulin sensitivity); flow cytometry for macrophage polarization; cytokine expression analysis","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined metabolic and inflammatory phenotypes using multiple orthogonal readouts; single lab","pmids":["28932870"],"is_preprint":false},{"year":2017,"finding":"KLK7 exhibits chymotryptic-like cleavage preferences with preference for hydrophobic residues at P2-P1 (non-prime) subsites and hydrophilic residues in prime subsites (P1'-P2'); single S195A active-site mutant retains residual catalytic activity, requiring double mutation (S195A + D102N) to achieve true catalytic inactivity.","method":"PICS (Proteomic Identification of Cleavage Sites) mass spectrometry-based approach using human proteome-derived peptide libraries; kinetic characterization of wild-type and catalytic triad mutants (kcat/KM determination)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical characterization with active-site mutagenesis and quantitative kinetics; comprehensive proteome-scale substrate profiling","pmids":["28754951"],"is_preprint":false},{"year":2019,"finding":"In-depth proteomic analysis identified 16 novel putative KLK7 substrates in ovarian cancer cell secretome, including direct activation of pro-MMP10, hydrolysis of IGFBP6, and cleavage of thrombospondin 1 generating a potentially bioactive N-terminal fragment; MMP2 and IGFBP3 were confirmed as established substrates. KLK7-cleaved substrates are enriched in cell adhesion, extracellular matrix remodeling, and cell migration pathways.","method":"qPROTOMAP (SILAC-coupled proteomic topography); TAILS (Terminal Amine Isotopic Labeling of Substrates) for exact cleavage site determination; biochemical validation of selected substrates","journal":"Molecular & cellular proteomics","confidence":"High","confidence_rationale":"Tier 1 — two orthogonal quantitative proteomics approaches with biochemical validation; multiple substrates confirmed across two cell lines","pmids":["30705123"],"is_preprint":false},{"year":2019,"finding":"KLK7 is a direct target of miR-326 (negatively regulated); in a Parkinson's disease mouse model, KLK7 expression is elevated and activates the MAPK signaling pathway (p38, ERK, JNK, caspase-3), promoting dopaminergic neuron apoptosis; silencing KLK7 or overexpressing miR-326 reduces MAPK pathway activation and neuronal apoptosis.","method":"PD mouse model; miR-326 mimic/inhibitor treatment; siRNA-KLK7 knockdown; luciferase reporter assay (miR-326/KLK7 3'UTR); measurement of dopamine metabolites; MAPK pathway protein analysis by Western blot","journal":"Journal of molecular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2-3 — validated miRNA-target relationship with pathway analysis in vivo; KLK7-MAPK link established by KD but mechanism of KLK7 activating MAPK not biochemically resolved","pmids":["31270675"],"is_preprint":false},{"year":2020,"finding":"IL-13 induces KLK7 transcription in keratinocytes via the ERK1/2 MAPK pathway activating the transcription factor EGR-1, which binds directly to an EGR-1-binding sequence (EBS) in the KLK7 promoter; point mutation of the EBS abolishes IL-13-induced KLK7 promoter activity; EGR1 knockout mice show reduced KLK7 expression in AD-like skin lesions.","method":"Promoter luciferase reporter assay with EBS point mutation; EGR-1 ChIP (implied by direct binding); shRNA knockdown of EGR1; Egr1 knockout mouse model of AD-like dermatitis; ERK inhibitor epistasis","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — promoter mutagenesis, TF knockdown, and KO mouse with concordant phenotype; multiple orthogonal approaches in single study","pmids":["33276948"],"is_preprint":false},{"year":2021,"finding":"A quenched phosphonate activity-based probe (KLK7-qABP) was developed that specifically detects active (but not inactive) KLK7 in vitro, providing a tool to monitor KLK7 enzymatic activity.","method":"Synthesis of mixed alkyl aryl phosphonate probe; in vitro activity-based protein profiling against recombinant KLK7","journal":"Organic & biomolecular chemistry","confidence":"Medium","confidence_rationale":"Tier 1 — direct active-site labeling tool validated in vitro; single lab, no in vivo validation yet","pmids":["34308939"],"is_preprint":false},{"year":2022,"finding":"Inhibitory antibodies against KLK5 and KLK7 protect against skin inflammation in mouse models of Netherton syndrome and atopic dermatitis; combined anti-KLK5/7 bispecific antibody promotes skin barrier integrity and reduces inflammation. Crystal structure of KLK5 bound to the inhibitory Fab revealed allosteric inhibition distal to the active site, demonstrating a non-active-site inhibition mechanism for kallikrein-family proteases.","method":"Antibody discovery and engineering; mouse NS and AD models; skin barrier integrity assays; inflammation markers; X-ray crystallography of KLK5-Fab complex","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional validation in multiple mouse disease models; bispecific antibody demonstrates joint KLK5/7 role; allosteric mechanism structurally defined","pmids":["36516271"],"is_preprint":false},{"year":2023,"finding":"KLK7 expression in keratinocytes is regulated by TNF signaling; inhibition of KLK7 expression decreases proinflammatory responses to TNF in keratinocytes, placing KLK7 downstream of TNF in psoriatic inflammation.","method":"KLK7 siRNA knockdown in keratinocytes; TNF stimulation assays; measurement of proinflammatory cytokine responses; pharmacogenetic study with functional validation","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with defined inflammatory phenotype; mechanistic link to TNF pathway established functionally; single lab","pmids":["37672660"],"is_preprint":false},{"year":2024,"finding":"KLK7 undergoes autolysis at two sites in the 170 and 99 loops (chymotrypsinogen numbering), leading to loss of enzymatic activity; KLK7 cleaves and inactivates mast cell chymase; KLK7 hydrolyzes multiple cytokines including IFN-α, IFN-β, IFN-γ, IL-28A/IFN-λ2, IL-20, IL-22, and IL-27 (predominantly interferon and IL-10 families).","method":"Protease-specific inhibitors; active-site variants; in vitro cleavage assays; protein BLAST for substrate identification; activity measurements post-cleavage","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with inhibitors and active-site variants identifying autolysis sites and novel substrates including cytokines and mast cell proteases","pmids":["39655764"],"is_preprint":false},{"year":2025,"finding":"KLK5 and KLK7 drive HPV-dependent cervical carcinogenesis; their absence ameliorates the HPV phenotype through modulation of KLK14 activation; KLK14 then activates PAR-2-dependent RhoA and NF-κB signaling pathways to exert pro-tumorigenic effects, placing KLK7 upstream of KLK14 activation in a protease cascade governing cervical carcinogenesis.","method":"Genetically engineered mice (KLK5/KLK7 double knockout); bulk RNA-seq; reporter assays for RhoA and NF-κB; human cervical biopsy expression analysis","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in mouse model with pathway reporter assays; single lab","pmids":["40753921"],"is_preprint":false},{"year":2025,"finding":"KLK7 in macrophages promotes inflammatory macrophage polarization and migration in visceral adipose tissue during obesity; macrophage-specific KLK7 knockout (KLK7MKO) reduces pro-inflammatory gene expression, restricts macrophage migration by increasing cell adhesion, and decreases immune cell infiltration into epididymal adipose tissue of HFD-fed mice.","method":"Macrophage-specific conditional KLK7 knockout (Cre-lox); HFD mouse model; flow cytometry for macrophage subsets; inflammatory gene expression analysis; cell adhesion assays; correlation with human visceral adipose tissue transcriptomics (n=1143)","journal":"Metabolism: clinical and experimental","confidence":"High","confidence_rationale":"Tier 2 — clean cell-type-specific KO with defined mechanistic phenotype (migration, adhesion, polarization) validated in mice and correlated in large human cohort","pmids":["40154838"],"is_preprint":false},{"year":2025,"finding":"KLK7 promotes epithelial-mesenchymal transition (EMT) in papillary thyroid cancer cells via the MAPK/ERK pathway; silencing KLK7 reduces ERK1/2 phosphorylation, suppresses EMT markers, and decreases proliferation, migration, and invasion in vitro and in vivo.","method":"KLK7 siRNA knockdown; immunohistochemistry; growth curve analysis; Western blot for ERK1/2 phosphorylation and EMT markers; nude mouse xenograft model","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with defined pathway (MAPK/ERK) and EMT phenotype in vitro and in vivo; single lab","pmids":["39991575"],"is_preprint":false},{"year":2025,"finding":"KLK7 overexpression in colorectal cancer cells enhances peritoneal dissemination in vivo; in vitro, it increases proliferation, migration, spheroid formation, adhesion to ECM proteins, and upregulates moesin (MSN) and integrin subunits, indicating cytoskeletal remodeling and altered matrix interactions.","method":"Stable KLK7 overexpression; xenograft peritoneal metastasis mouse model; Peritoneal Cancer Index scoring; in vitro migration, adhesion, spheroid assays; gene expression analysis","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 — gain-of-function in vivo and in vitro with specific molecular targets identified (moesin, integrins); single lab","pmids":["41335524"],"is_preprint":false},{"year":2025,"finding":"NMDA receptor signaling in astrocytes negatively regulates KLK7 mRNA expression through NF-κB; inhibition of NF-κB signaling increases KLK7 expression in astrocytes and promotes degradation of amyloid-β (Aβ), identifying KLK7 as an astrocyte-derived Aβ-degrading protease; in vivo NF-κB inhibitor injection upregulates Klk7 and reduces Aβ levels.","method":"NMDA receptor antagonist (memantine) and NF-κB inhibitor treatment of astrocytes; KLK7 expression analysis; Aβ degradation assays; in vivo mouse model with NF-κB inhibitor injection and Aβ measurement","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — identifies novel KLK7 substrate (Aβ) and upstream regulatory pathway with in vivo validation; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"Loss of store-operated Ca2+ entry (SOCE) via Stim1/2 knockout in mouse epidermis leads to elevated Klk7 levels and increased chymotrypsin-like serine protease activity, accompanied by alterations in desmoglein 1 and hyperkeratosis; this places SOCE/Ca2+ signaling upstream of KLK7 activity in epidermal barrier maintenance.","method":"Epithelial-specific Stim1/2 conditional knockout mice; RNA-seq; transepidermal water loss measurement; in situ protease activity assays; immunofluorescence for Dsg1","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined phenotype linking Ca2+ signaling to KLK7 activity; preprint, not peer-reviewed","pmids":[],"is_preprint":true},{"year":2026,"finding":"Substrate-analog and non-peptide inhibitors of KLK7 with Ki values <100 nM were developed; a key determinant of inhibitor selectivity is alanine at position 190 in the S1 pocket. KLK7 inhibition blocks chemokine cleavage and moesin gene upregulation by KLK7, confirming these as functional downstream activities; mutating T190A in murine Klk7 restored human-inhibitor potency, validating a species-adapted model.","method":"Medicinal chemistry synthesis; Ki measurement; KLK7 crystal structure-guided design; site-directed mutagenesis (T190A); cell-based assays for chemokine cleavage and moesin upregulation; ovarian cancer xenograft mouse model","journal":"Biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — structure-guided mutagenesis with Ki determination and functional cell-based validation; identifies structural basis of S1 pocket selectivity","pmids":["41855304"],"is_preprint":false}],"current_model":"KLK7 is a chymotrypsin-like serine protease secreted from lamellar granules in the stratum corneum (regulated by LEKTI/SPINK5 in a pH-dependent manner and transcriptionally by the IL-13–ERK–EGR1 and TNF signaling axes) that drives desquamation by directly cleaving corneodesmosomal proteins CDSN and DSC1 (and DSG1 after KLK5-mediated activation of its proform); beyond skin, KLK7 cleaves cytokines (IFNs, IL-10 family members), mast cell chymase, ECM proteins (via pro-MMP10 activation, IGFBP6/thrombospondin-1 cleavage), and amyloid-β in astrocytes, and promotes inflammation and tumor progression through integrin downregulation, MAPK/ERK-driven EMT, PAR-2/RhoA/NF-κB signaling (via KLK14 activation), and macrophage polarization/migration in adipose tissue."},"narrative":{"teleology":[{"year":1996,"claim":"Identification of KLK7 (SCCE) as a chymotrypsin-like serine protease of the stratum corneum established the molecular identity of the desquamation enzyme and placed it in a kallikrein gene cluster on 19q13.","evidence":"cDNA cloning and sequence homology analysis from human stratum corneum","pmids":["8898378"],"confidence":"Medium","gaps":["no substrates identified","no in vitro enzymatic characterization","regulation unknown"]},{"year":2004,"claim":"Reconstituted cleavage assays resolved which corneodesmosomal targets KLK7 acts on directly (CDSN, DSC1 but not DSG1) and showed that KLK5 activates pro-KLK7, establishing a protease activation cascade driving desquamation.","evidence":"In vitro cleavage assays with recombinant and epidermal substrates at acidic pH; proform activation assays","pmids":["15140227"],"confidence":"High","gaps":["in vivo confirmation of sequential activation not yet shown","cleavage site mapping not performed in this study"]},{"year":2005,"claim":"Subcellular imaging revealed that KLK7 resides in lamellar granules and is secreted after LEKTI, explaining how premature desquamation is prevented and why LEKTI loss (Netherton syndrome) leads to barrier failure.","evidence":"Confocal and immunoelectron microscopy of normal and Netherton syndrome skin biopsies","pmids":["15675955"],"confidence":"High","gaps":["mechanism of secretion timing not defined","whether impaired secretion occurs in diseases other than Netherton syndrome unknown at this point"]},{"year":2007,"claim":"Kinetic characterization of LEKTI fragment–KLK interactions revealed pH-dependent release of active KLK5 (and differential inhibition of KLK7 and KLK14), providing the molecular gating mechanism that couples skin acidification to desquamation.","evidence":"Biochemical inhibition kinetics and pH-dependent binding/release assays with furin-processed LEKTI fragments","pmids":["17596512"],"confidence":"High","gaps":["which specific LEKTI fragments are the dominant KLK7 inhibitors in vivo remains unclear","structural basis of pH-dependent release not determined"]},{"year":2017,"claim":"Comprehensive substrate-site profiling defined KLK7's chymotryptic specificity (hydrophobic P2-P1, hydrophilic P1'-P2') and showed that the canonical S195A active-site mutant retains residual activity, requiring a double catalytic-triad mutation for true inactivation.","evidence":"PICS mass spectrometry-based cleavage profiling; kinetic characterization of wild-type and active-site mutants","pmids":["28754951"],"confidence":"High","gaps":["extended subsite cooperativity not fully modeled","no crystal structure of KLK7 with a substrate analog at this time"]},{"year":2017,"claim":"Adipose-tissue-specific Klk7 knockout demonstrated a non-skin role: KLK7 promotes weight gain, insulin resistance, and pro-inflammatory macrophage polarization under high-fat diet, establishing KLK7 as a metabolic regulator.","evidence":"Conditional Cre-lox KO in mouse adipose tissue with metabolic phenotyping and macrophage flow cytometry","pmids":["28932870"],"confidence":"High","gaps":["direct adipose substrates of KLK7 not identified","mechanism linking protease activity to macrophage polarization unresolved"]},{"year":2019,"claim":"Quantitative degradomics expanded the KLK7 substrate repertoire beyond corneodesmosomes to ECM remodeling mediators (pro-MMP10 activation, IGFBP6, thrombospondin-1 cleavage) in ovarian cancer secretomes, linking KLK7 to invasion and matrix turnover.","evidence":"qPROTOMAP and TAILS quantitative proteomics in OVMZ6 and SKOV3 ovarian cancer cells with biochemical validation","pmids":["30705123"],"confidence":"High","gaps":["in vivo relevance of each novel substrate not confirmed","catalytic efficiency for individual substrates not fully quantified"]},{"year":2020,"claim":"Identification of the IL-13–ERK1/2–EGR1 transcriptional axis controlling KLK7 promoter activity explained how Th2 inflammation upregulates KLK7 in atopic dermatitis skin.","evidence":"Promoter-reporter assay with EBS point mutation, EGR1 knockdown, Egr1 KO mouse AD model, ERK inhibitor epistasis in keratinocytes","pmids":["33276948"],"confidence":"High","gaps":["whether other Th2 cytokines (IL-4, IL-31) use the same promoter element is unknown","chromatin-level regulation not examined"]},{"year":2022,"claim":"Therapeutic proof-of-concept was achieved with inhibitory anti-KLK5/KLK7 bispecific antibodies that restored skin barrier integrity and reduced inflammation in Netherton syndrome and AD mouse models, confirming KLK5 and KLK7 as co-drivers of skin inflammatory disease.","evidence":"Antibody engineering; mouse NS and AD models; X-ray crystallography of KLK5–Fab complex revealing allosteric inhibition","pmids":["36516271"],"confidence":"High","gaps":["structural basis of antibody–KLK7 interaction not resolved (only KLK5–Fab crystallized)","human clinical efficacy unknown"]},{"year":2024,"claim":"Discovery of KLK7-mediated hydrolysis of interferons (IFN-α, -β, -γ), IL-10-family cytokines, and mast cell chymase broadened KLK7's functional scope to immune modulation and revealed that KLK7 undergoes autolytic inactivation at two specific loops.","evidence":"In vitro cleavage assays with active-site variants and protease-specific inhibitors; substrate identification by protein BLAST","pmids":["39655764"],"confidence":"High","gaps":["physiological relevance of cytokine cleavage in vivo not demonstrated","whether autolysis is a regulatory mechanism or artifact at high concentrations not resolved"]},{"year":2025,"claim":"Multiple 2025 studies extended KLK7's disease roles: a KLK5/KLK7→KLK14→PAR-2/NF-κB cascade drives HPV-dependent cervical carcinogenesis, macrophage-specific KLK7 promotes inflammatory polarization/migration in obese adipose tissue, KLK7 drives MAPK/ERK-dependent EMT in thyroid cancer, and KLK7 overexpression enhances peritoneal dissemination in colorectal cancer.","evidence":"KLK5/KLK7 double-KO mice with RNA-seq and pathway reporters; macrophage-specific Klk7 KO with HFD; KLK7 siRNA with ERK/EMT readouts in thyroid cancer; KLK7 overexpression xenograft peritoneal metastasis model","pmids":["40753921","40154838","39991575","41335524"],"confidence":"Medium","gaps":["direct KLK7 substrates mediating EMT, macrophage migration, and peritoneal dissemination not individually identified","KLK7 versus KLK5 individual contributions hard to deconvolute in double-KO cervical cancer model"]},{"year":2026,"claim":"Structure-guided development of potent (<100 nM) KLK7 inhibitors identified Ala190 in the S1 pocket as the key selectivity determinant and confirmed chemokine cleavage and moesin upregulation as functional downstream outputs of KLK7 catalytic activity.","evidence":"Medicinal chemistry; Ki measurement; T190A mutagenesis restoring inhibitor potency in murine Klk7; cell-based chemokine and moesin assays; ovarian cancer xenograft","pmids":["41855304"],"confidence":"High","gaps":["no co-crystal structure of KLK7 with the inhibitor reported","in vivo pharmacokinetics and therapeutic window not established"]},{"year":null,"claim":"Key unresolved questions include the identity of direct KLK7 substrates mediating its pro-tumorigenic and metabolic effects, the physiological significance of cytokine and amyloid-β cleavage in vivo, structural characterization of KLK7–inhibitor and KLK7–antibody complexes, and the relative contributions of KLK7 versus other kallikreins in protease cascades across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no KLK7 crystal structure with a bound substrate or therapeutic antibody","in vivo substrate validation in non-skin contexts largely absent","whether autolysis is physiologically regulated remains unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5,6,12,13,19,26]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,3,12,19]}],"localization":[{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[4,10]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,13,19]}],"pathway":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[13,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,20,22]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,6,12]}],"complexes":[],"partners":["KLK5","SPINK5","CDSN","DSC1","DSG1","KLK14","MMP10","EGR1"],"other_free_text":[]},"mechanistic_narrative":"KLK7 is a secreted chymotrypsin-like serine protease that functions as a central effector of epidermal desquamation and participates in extracellular proteolytic cascades in multiple tissues. In the stratum corneum, KLK7 is released from lamellar granules and directly cleaves the corneodesmosomal proteins corneodesmosin (CDSN) and desmocollin 1 (DSC1), with its activity gated by pH-dependent inhibition by LEKTI/SPINK5 fragments and by upstream activation of its proform by KLK5 [PMID:15140227, PMID:17596512, PMID:15675955]. Beyond skin barrier homeostasis, KLK7 cleaves interferons, IL-10-family cytokines, mast cell chymase, IGFBP6, thrombospondin-1, and pro-MMP10, and its transcription is regulated by IL-13–ERK–EGR1, TNF, and NF-κB signaling axes [PMID:39655764, PMID:30705123, PMID:33276948, PMID:37672660]. In disease contexts, KLK7 promotes inflammatory macrophage polarization and migration in adipose tissue, drives MAPK/ERK-dependent epithelial–mesenchymal transition in cancer, and participates in a KLK5/KLK7→KLK14→PAR-2/NF-κB protease cascade in cervical carcinogenesis [PMID:40154838, PMID:39991575, PMID:40753921]."},"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'. 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Research","url":"https://pubmed.ncbi.nlm.nih.gov/16203767","citation_count":65,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12232761","id":"PMC_12232761","title":"Immunofluorometric quantitation and histochemical localisation of kallikrein 6 protein in ovarian cancer tissue: a new independent unfavourable prognostic biomarker.","date":"2002","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12232761","citation_count":63,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23173,"output_tokens":4619,"usd":0.069402},"stage2":{"model":"claude-opus-4-6","input_tokens":8158,"output_tokens":3157,"usd":0.179572},"total_usd":0.571504,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":37215,"output_tokens":7897,"usd":0.11505},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":11019,"output_tokens":3329,"usd":0.20748}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"KLK7 (SCCE) directly cleaves corneodesmosin (CDSN) and desmocollin 1 (DSC1) in vitro at acidic pH, but cannot degrade desmoglein 1 (DSG1); glycosylation of CDSN does not protect it from KLK7 proteolysis. Additionally, KLK5 (SCTE) can activate the proform of KLK7, suggesting a protease cascade in desquamation.\",\n      \"method\": \"In vitro protease cleavage assays with recombinant and epidermal substrates at acidic pH, including deglycosylated forms of CDSN\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic assay with multiple substrates and controls, replicated across substrate forms\",\n      \"pmids\": [\"15140227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14; the interaction is pH-dependent, with active KLK5 (and by extension KLK7) released from the LEKTI complex at acidic pH, establishing a mechanism by which the epidermal pH gradient regulates corneodesmosomal cleavage and desquamation.\",\n      \"method\": \"Biochemical analysis of LEKTI fragment identity; kinetic inhibition assays of KLK7 activity; pH-shift release experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — kinetics analysis plus mechanistic pH-shift experiment, multiple orthogonal methods\",\n      \"pmids\": [\"17596512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In normal epidermis, KLK7 and KLK5 are localized within lamellar granules but are spatially separated from LEKTI, with LEKTI secreted earlier than KLK7/KLK5, preventing premature loss of stratum corneum integrity; in Netherton syndrome skin lacking LEKTI, an abnormal split appears in the superficial stratum granulosum.\",\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 — direct localization by immunoelectron microscopy with functional consequence shown in disease tissue\",\n      \"pmids\": [\"15675955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inhibitory antibodies against KLK7 (and KLK5) are protective in mouse models of Netherton syndrome and atopic dermatitis; a crystal structure of KLK5 bound to its inhibitory Fab revealed allosteric inhibition distal to the active site, a mechanistic insight applicable to KLK7 therapeutic targeting.\",\n      \"method\": \"Mouse models of NS and AD with antibody treatment; crystal structure of KLK5–Fab complex; bispecific antibody engineering with potent inhibition of human KLK5 and KLK7\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vivo functional rescue with multiple orthogonal methods\",\n      \"pmids\": [\"36516271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KLK7 cleaves MMP2, IGFBP3, directly activates pro-MMP10, hydrolyzes IGFBP6, and cleaves thrombospondin 1 generating a potentially bioactive N-terminal fragment in ovarian cancer cell secretome; these substrates are enriched in cell adhesion, ECM remodeling, and cell migration processes.\",\n      \"method\": \"Quantitative proteomics (PROTOMAP-SILAC and TAILS) of SKOV-3 and OVMZ-6 ovarian cancer cell secretomes; biochemical validation of individual substrates\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — two technically divergent quantitative proteomics approaches plus biochemical substrate validation\",\n      \"pmids\": [\"30705123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLK7 exerts chymotryptic-like cleavage preferences with preference for hydrophobic residues at P2-P1 and hydrophilic residues in prime subsites; single S195A catalytic triad mutant retains residual activity, while the double mutant (S195A + D102N) fully abolishes activity.\",\n      \"method\": \"Mass spectrometry-based PICS (Proteomic Identification of protease Cleavage Sites) using human proteome-derived peptide libraries; kinetic characterization of active-site mutants\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic characterization with active-site mutagenesis and MS-based substrate profiling\",\n      \"pmids\": [\"28754951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In atopic dermatitis lesional skin, KLK7 secretion from lamellar granules is impaired and LEKTI expression is upregulated, leading to ineffective KLK7 activation and abnormal corneodesmosin degradation patterns, resulting in compact hyperkeratosis despite elevated KLK7 protein levels.\",\n      \"method\": \"Western blot of stratum corneum, in situ zymography of tape-stripped corneocytes, immunostaining, electron microscopy\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking impaired secretion to functional proteolysis defect in human tissue\",\n      \"pmids\": [\"27769847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adipose tissue-specific ablation of Klk7 in mice fed a high-fat diet results in reduced weight gain, improved whole-body insulin sensitivity, higher energy expenditure, reduced pro-inflammatory cytokine expression, and increased anti-inflammatory M2 macrophage polarization in epididymal adipose tissue, identifying KLK7 as a regulator of adipose tissue inflammation and metabolic function.\",\n      \"method\": \"Conditional adipose-specific Klk7 knockout mice (ATKlk7-/-); metabolic phenotyping, adipokine measurements, macrophage polarization analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined metabolic and inflammatory phenotypic readouts\",\n      \"pmids\": [\"28932870\"],\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 and inactivates mast cell chymase; KLK7 hydrolyzes cytokines including IFN-α, IFN-β, IFN-γ, IL-28A/IFN-λ2, IL-20, IL-22, and IL-27.\",\n      \"method\": \"Protease-specific inhibitors, active-site variants, in vitro cleavage assays with mast cell proteases and cytokines\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro assay with mutagenesis, single lab, novel substrates without full biological validation\",\n      \"pmids\": [\"39655764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KLK7 encodes a secreted chymotryptic serine protease expressed in skin, CNS, kidney, mammary, and salivary glands; its expression is up-regulated by estrogens and glucocorticoids in breast carcinoma cells (BT-474), and it maps to chromosomal locus 19q13.3-q13.4 within the kallikrein gene cluster.\",\n      \"method\": \"Genomic characterization, RT-PCR tissue expression profiling, hormonal treatment of BT-474 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — expression and genomic characterization with hormonal regulation, 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 cell adhesion to vitronectin and fibronectin, and confers paclitaxel resistance independent of MEK1/2 signaling.\",\n      \"method\": \"Stable transfection, quantitative gene/protein expression, confocal microscopy, cell adhesion assays, chemosensitivity assays, MEK1/2 inhibitor treatment\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods but KLK7-specific contribution not isolated from other KLKs\",\n      \"pmids\": [\"22964375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLK7 overexpression in HT29 colon cancer cells increases cell proliferation in vitro and accelerates tumor growth in nude mice, establishing KLK7 as a proliferative factor in colon cancer.\",\n      \"method\": \"Stable KLK7 transfection in HT29 cells; proliferation assays; subcutaneous xenograft in nude mice with Ki-67 staining\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function both in vitro and in vivo with defined proliferative readout\",\n      \"pmids\": [\"25153388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-13 induces KLK7 transcription in keratinocytes via the ERK1/2 MAPK pathway activating transcription factor EGR-1, which binds directly to an EGR-1-binding sequence (EBS) in the KLK7 promoter; disruption of EBS or EGR1 knockdown abrogates IL-13-induced KLK7 expression.\",\n      \"method\": \"Luciferase reporter assay with EBS point mutant; ChIP for EGR-1 binding; shRNA knockdown of EGR1; Egr1 knockout mice with AD-like skin lesions induced by DNCB\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including reporter, ChIP, KD, and in vivo KO validation\",\n      \"pmids\": [\"33276948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK7 and KLK5 drive HPV-dependent cervical carcinogenesis; absence of both KLK5 and KLK7 ameliorates the HPV-dependent phenotype by reducing KLK14 activation, which in turn signals through PAR-2-dependent RhoA and NF-κB pathways.\",\n      \"method\": \"Genetically engineered mice, bulk RNA-seq, reporter assays, analysis of human cervical cancer biopsies\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in mouse model with defined pathway placement, KLK7 contribution not fully isolated from KLK5\",\n      \"pmids\": [\"40753921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Macrophage-specific KLK7 knockout reduces pro-inflammatory gene expression in macrophages, restricts macrophage migration by increasing cell adhesion, and decreases inflammatory macrophage infiltration into visceral adipose tissue in obese mice.\",\n      \"method\": \"Macrophage-specific KLK7 conditional KO mice (KLK7MKO); HFD model; inflammatory marker quantification; adhesion and migration assays\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with defined mechanistic phenotype (adhesion, migration, inflammatory gene expression) in vivo and in vitro\",\n      \"pmids\": [\"40154838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK7 promotes epithelial-mesenchymal transition (EMT) and invasiveness in papillary thyroid cancer cells via the MAPK/ERK signaling pathway; KLK7 silencing reduces ERK1/2 phosphorylation and suppresses EMT markers.\",\n      \"method\": \"KLK7 knockdown in PTC cell lines; phospho-ERK1/2 western blot; EMT marker profiling; proliferation, migration, invasion assays; nude mouse xenograft\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined pathway (MAPK/ERK-EMT) supported by in vivo data\",\n      \"pmids\": [\"39991575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NMDA receptor signaling in astrocytes negatively regulates KLK7 mRNA expression via NF-κB; inhibition of NF-κB increases KLK7 expression and promotes amyloid-β degradation in vitro and in vivo, identifying KLK7 as an astrocyte-derived Aβ-degrading protease regulated by the NMDA receptor-NF-κB axis.\",\n      \"method\": \"NF-κB inhibitor treatment of astrocytes; KLK7 expression quantification; Aβ degradation assays; in vivo NF-κB inhibitor injection with Klk7 expression and Aβ level measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo mechanistic pathway identification, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.03.02.641088\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Antileukoprotease (ALP/SLPI) is coordinately expressed with KLK7 (SCCE) in ovarian tumors and functions as a specific inhibitor of SCCE, suggesting a protease-inhibitor regulatory relationship in ovarian cancer.\",\n      \"method\": \"Northern blot, semi-quantitative PCR, immunohistochemistry of ovarian tumor tissues\",\n      \"journal\": \"International journal of gynecological cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression correlation in tumor tissue, no direct biochemical inhibition assay performed in this study\",\n      \"pmids\": [\"11906548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In mice with epidermis-specific STIM1/2 knockout (impaired store-operated Ca2+ entry), Klk7 levels are elevated leading to increased chymotrypsin-like serine protease activity, altered desmoglein 1 processing, and impaired epidermal barrier function with hyperkeratosis.\",\n      \"method\": \"Epithelial-specific Stim1/2 conditional KO mice; RNA-seq; Klk7 protein quantification; in situ serine protease activity assay; TEWL measurement; biotinylated tracer diffusion\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined mechanistic link between calcium signaling, Klk7 activity, and barrier function, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.10.14.681588\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KLK7 is a secreted chymotrypsin-like serine protease that functions as a key effector of epidermal desquamation by directly cleaving corneodesmosome proteins (corneodesmosin, desmocollin 1) after activation of its proform by KLK5; its activity is tightly regulated by the pH-dependent inhibitor LEKTI (encoded by SPINK5), by spatial separation within lamellar granules, and by EGR-1-mediated transcriptional control downstream of IL-13/ERK signaling; beyond the skin, KLK7 promotes cancer progression through integrin downregulation, ECM remodeling (cleavage of MMP2, IGFBP3, pro-MMP10, thrombospondin 1), and EMT via MAPK/ERK; in adipose tissue and macrophages it drives pro-inflammatory polarization and immune cell infiltration; and in astrocytes it degrades amyloid-β under NMDA receptor–NF-κB regulation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nKEEP (about KLK7): Papers [1],[2],[3],[6],[9-from-main-corpus],[11],[13],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[31],[34],[35],[36],[38],[40],[41] from main corpus, plus gene2pubmed [6],[7],[8]\n\nMore carefully:\n- Papers clearly about KLK7: [1],[2],[3],[6],[9],[11],[13],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[31],[34],[35],[36],[38],[40],[41]\n- Papers about KLK6 (alias collision in gene2pubmed): gene2pubmed [10],[12],[13],[14],[16],[17],[18],[19],[20],[21],[23],[24],[25],[26],[27],[28],[29],[30] — EXCLUDE (KLK6/neurosin papers)\n- gene2pubmed [1],[2],[3],[4],[5] — generic/cDNA collections, no KLK7 mechanism — EXCLUDE\n- gene2pubmed [6] (Borgoño 2006) — discusses KLK7 and KLK5 desquamation — KEEP\n- gene2pubmed [7] (Anisowicz 1996) — describes \"protease M\" which maps to KLK6 locus — EXCLUDE\n- gene2pubmed [8] (Oikonomopoulou 2006) — PAR activation by kallikreins, tests hK5, hK6, hK14 but not hK7 specifically — EXCLUDE\n- gene2pubmed [15] (nomenclature) — EXCLUDE (no mechanism)\n- gene2pubmed [9] (Yamashiro 1997, neurosin = KLK6) — EXCLUDE\n- gene2pubmed [11] (Little 1997, Zyme = KLK6) — EXCLUDE\n\nMain corpus papers about KLK5/6 primarily: [4] mentions KLK7 variant transcripts — KEEP (describes KLK7 splice variants)\n[5] — lncRNA/ceRNA paper about NEAT1/KLK7 — KEEP (KLK7 is canonical target, functional assays)\n[12] — lncRNA FOXD2-AS1/KLK7 — KEEP\n[7],[8] — association/GWAS — EXCLUDE\n[10],[14],[28],[32] — expression/biomarker — EXCLUDE\n[29] — porcine KLK7 SNP/litter size — EXCLUDE (not mechanistic mammalian ortholog context relevant)\n[30] — cisplatin/KLK7 expression — EXCLUDE (no mechanism)\n[33] — pancreatic cancer KLK7 OE/KD phenotype — KEEP (functional)\n[17] — ALP/SLPI inhibitor of SCCE/KLK7 — KEEP\n[18] — hK7 and ALP in cervical cancer — EXCLUDE (IHC/expression)\n[37] — sheep horn KLK7 — EXCLUDE (SYMBOL COLLISION / non-human ortholog with incompatible context)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"KLK7 (SCCE/hK7) was identified as a chymotrypsin-like serine protease expressed in the stratum corneum, responsible for the cell shedding (desquamation) process; the gene was localized to chromosome 19q13.3.\",\n      \"method\": \"cDNA cloning, sequence homology analysis, differential display\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — original cloning with sequence characterization; single lab foundational discovery\",\n      \"pmids\": [\"8898378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"KLK7 encodes a secreted chymotryptic serine protease (SCCE/hK7) whose expression is upregulated by estrogens and glucocorticoids in breast carcinoma cells (BT-474), and is expressed in brain, kidney, mammary and salivary glands in addition to skin; the gene maps to 19q13.3-q13.4 between KLK6 and KLK8.\",\n      \"method\": \"RT-PCR, Northern blot, genomic organization analysis, hormonal stimulation assays in BT-474 cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct hormonal regulation demonstrated in cell-based assay; single lab\",\n      \"pmids\": [\"10974542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Antileukoprotease (ALP/SLPI) is co-expressed with KLK7 (SCCE) in ovarian tumors and has been identified as a specific inhibitor of KLK7 enzymatic activity.\",\n      \"method\": \"Northern blot, semi-quantitative PCR, immunohistochemistry; correlation of SCCE and ALP expression\",\n      \"journal\": \"International journal of gynecological cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — inhibitor relationship inferred from co-expression; direct Ki measurement not reported in this paper\",\n      \"pmids\": [\"11906548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"KLK7 (SCCE/hK7) directly cleaves the corneodesmosomal proteins corneodesmosin (CDSN) and desmocollin 1 (DSC1) at acidic pH (mimicking stratum corneum pH), but cannot degrade desmoglein 1 (DSG1) alone; KLK5 (SCTE) activates the proform of KLK7 (pro-SCCE) and enables degradation of all three corneodesmosomal components including DSG1. Oligosaccharide residues on CDSN do not protect it from KLK7 proteolysis.\",\n      \"method\": \"In vitro protease cleavage assays with recombinant and epidermal forms of substrates at acidic pH; enzymatic deglycosylation experiments; SDS-PAGE analysis of cleavage products\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro cleavage assays with defined substrates and proform activation, replicated with multiple substrate forms\",\n      \"pmids\": [\"15140227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KLK7 is localized to lamellar granules in the stratum granulosum separately from LEKTI, with LEKTI secreted earlier than KLK7 and KLK5; this spatial and temporal separation ensures LEKTI is present extracellularly before KLK7 is released, preventing premature desquamation. In Netherton syndrome skin lacking LEKTI, an abnormal split appears in the superficial stratum granulosum.\",\n      \"method\": \"Confocal laser scanning microscopy and immunoelectron microscopy of normal and Netherton syndrome skin biopsies\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dual-modality direct localization with functional consequence demonstrated in disease skin; replicated across normal and NS cases\",\n      \"pmids\": [\"15675955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Multiple KLK family members including KLK7 participate in desquamation through cleavage of desmoglein 1 (within cadherin repeats, Ca2+-binding sites, and juxtamembrane region) and are regulated by LEKTI fragments; KLK7 digests the ectodomain of desmoglein 1 in vitro. KLK7 was not significantly inhibited by secretory leukocyte protease inhibitor (SLPI) or elafin in contrast to earlier reports.\",\n      \"method\": \"In vitro protease digestion assays with recombinant desmoglein 1 ectodomain; Ki measurements with recombinant LEKTI fragments; SDS-PAGE\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro cleavage and inhibition kinetics with defined recombinant proteins\",\n      \"pmids\": [\"17158887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"LEKTI is processed by furin into multiple single- and multi-domain fragments (D1, D5, D6, D8-D11, D9-D15); these fragments specifically and differentially inhibit KLK5, KLK7, and KLK14 but not other serine proteases tested. The KLK5-LEKTI(D8-D11) interaction is rapid, tight, and functionally irreversible; crucially, acidic pH (as found in the superficial stratum corneum) causes release of active KLK5 from the inhibitory complex, providing a pH-dependent gating mechanism for KLK-mediated corneodesmosomal cleavage.\",\n      \"method\": \"Biochemical inhibition kinetics; furin cleavage assays; pH-dependent binding/release assays; functional protease activity assays on KLK5, KLK7, KLK14\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with kinetic analysis and pH-dependent mechanistic dissection; replicated across multiple LEKTI fragments\",\n      \"pmids\": [\"17596512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"KLK5 and KLK7 generate tissue-specific (pancreas) transcripts driven by alternative promoters distinct from those used in skin or ovary; immunohistochemistry localizes both enzymes predominantly to acinar cells of the exocrine pancreas, suggesting roles in digestion.\",\n      \"method\": \"Northern blot of 19 normal human tissues; in silico promoter analysis; immunohistochemistry; RT-PCR\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization by IHC and molecular characterization of alternative transcripts; single lab, no functional reconstitution\",\n      \"pmids\": [\"18163887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Combined overexpression of KLK4, KLK5, KLK6, and KLK7 in ovarian cancer cells (OV-MZ-6) downregulates α5β1 and αvβ3 integrin expression, reduces cell adhesion to vitronectin and fibronectin, and confers paclitaxel resistance (not carboplatin resistance) through reduced apoptotic stimuli; this resistance is independent of MEK1/2 signaling.\",\n      \"method\": \"Stable transfection; quantitative gene and protein expression; confocal microscopy; cell adhesion assays; chemosensitivity assays; MEK inhibitor (U0126) epistasis\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with genetic epistasis; combined KLK overexpression limits attribution specifically to KLK7\",\n      \"pmids\": [\"22964375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"KLK7 overexpression in HT29 colon cancer cells increases cell proliferation in vitro and tumor growth in vivo; KLK7 protein is aberrantly expressed and secreted in colon cancer tissues and cell lines but absent in normal colonic epithelium.\",\n      \"method\": \"Stable transfection with KLK7 expression plasmid; CCK-8 proliferation assay; subcutaneous xenograft in nude mice; Ki-67 staining; Western blot; immunofluorescence\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function with defined proliferative phenotype both in vitro and in vivo; single lab\",\n      \"pmids\": [\"25153388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In atopic dermatitis lesional skin, KLK7 secretion from lamellar granules is impaired despite increased total KLK7 protein levels, resulting in ineffective KLK activation and abnormal corneodesmosin degradation; concurrently, LEKTI expression is upregulated as a compensatory mechanism to prevent further barrier dysfunction.\",\n      \"method\": \"Western blot analysis of stratum corneum; in situ zymography on tape-stripped corneocytes; immunostaining; electron microscopy of lamellar granules\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods demonstrating impaired secretion with functional consequence; single lab\",\n      \"pmids\": [\"27769847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Adipose tissue-specific Klk7 knockout mice (ATKlk7-/-) show less weight gain, preferential subcutaneous adipose expansion, improved insulin sensitivity, higher energy expenditure, reduced pro-inflammatory cytokine expression, and increased anti-inflammatory M2 macrophages in epididymal adipose tissue under high-fat diet. KLK7 deficiency alters adipokine secretion including reduced circulating leptin.\",\n      \"method\": \"Conditional gene targeting (Cre-lox) in adipose tissue; metabolic phenotyping (glucose tolerance, insulin sensitivity); flow cytometry for macrophage polarization; cytokine expression analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined metabolic and inflammatory phenotypes using multiple orthogonal readouts; single lab\",\n      \"pmids\": [\"28932870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KLK7 exhibits chymotryptic-like cleavage preferences with preference for hydrophobic residues at P2-P1 (non-prime) subsites and hydrophilic residues in prime subsites (P1'-P2'); single S195A active-site mutant retains residual catalytic activity, requiring double mutation (S195A + D102N) to achieve true catalytic inactivity.\",\n      \"method\": \"PICS (Proteomic Identification of Cleavage Sites) mass spectrometry-based approach using human proteome-derived peptide libraries; kinetic characterization of wild-type and catalytic triad mutants (kcat/KM determination)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical characterization with active-site mutagenesis and quantitative kinetics; comprehensive proteome-scale substrate profiling\",\n      \"pmids\": [\"28754951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In-depth proteomic analysis identified 16 novel putative KLK7 substrates in ovarian cancer cell secretome, including direct activation of pro-MMP10, hydrolysis of IGFBP6, and cleavage of thrombospondin 1 generating a potentially bioactive N-terminal fragment; MMP2 and IGFBP3 were confirmed as established substrates. KLK7-cleaved substrates are enriched in cell adhesion, extracellular matrix remodeling, and cell migration pathways.\",\n      \"method\": \"qPROTOMAP (SILAC-coupled proteomic topography); TAILS (Terminal Amine Isotopic Labeling of Substrates) for exact cleavage site determination; biochemical validation of selected substrates\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — two orthogonal quantitative proteomics approaches with biochemical validation; multiple substrates confirmed across two cell lines\",\n      \"pmids\": [\"30705123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KLK7 is a direct target of miR-326 (negatively regulated); in a Parkinson's disease mouse model, KLK7 expression is elevated and activates the MAPK signaling pathway (p38, ERK, JNK, caspase-3), promoting dopaminergic neuron apoptosis; silencing KLK7 or overexpressing miR-326 reduces MAPK pathway activation and neuronal apoptosis.\",\n      \"method\": \"PD mouse model; miR-326 mimic/inhibitor treatment; siRNA-KLK7 knockdown; luciferase reporter assay (miR-326/KLK7 3'UTR); measurement of dopamine metabolites; MAPK pathway protein analysis by Western blot\",\n      \"journal\": \"Journal of molecular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — validated miRNA-target relationship with pathway analysis in vivo; KLK7-MAPK link established by KD but mechanism of KLK7 activating MAPK not biochemically resolved\",\n      \"pmids\": [\"31270675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-13 induces KLK7 transcription in keratinocytes via the ERK1/2 MAPK pathway activating the transcription factor EGR-1, which binds directly to an EGR-1-binding sequence (EBS) in the KLK7 promoter; point mutation of the EBS abolishes IL-13-induced KLK7 promoter activity; EGR1 knockout mice show reduced KLK7 expression in AD-like skin lesions.\",\n      \"method\": \"Promoter luciferase reporter assay with EBS point mutation; EGR-1 ChIP (implied by direct binding); shRNA knockdown of EGR1; Egr1 knockout mouse model of AD-like dermatitis; ERK inhibitor epistasis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter mutagenesis, TF knockdown, and KO mouse with concordant phenotype; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"33276948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A quenched phosphonate activity-based probe (KLK7-qABP) was developed that specifically detects active (but not inactive) KLK7 in vitro, providing a tool to monitor KLK7 enzymatic activity.\",\n      \"method\": \"Synthesis of mixed alkyl aryl phosphonate probe; in vitro activity-based protein profiling against recombinant KLK7\",\n      \"journal\": \"Organic & biomolecular chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct active-site labeling tool validated in vitro; single lab, no in vivo validation yet\",\n      \"pmids\": [\"34308939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inhibitory antibodies against KLK5 and KLK7 protect against skin inflammation in mouse models of Netherton syndrome and atopic dermatitis; combined anti-KLK5/7 bispecific antibody promotes skin barrier integrity and reduces inflammation. Crystal structure of KLK5 bound to the inhibitory Fab revealed allosteric inhibition distal to the active site, demonstrating a non-active-site inhibition mechanism for kallikrein-family proteases.\",\n      \"method\": \"Antibody discovery and engineering; mouse NS and AD models; skin barrier integrity assays; inflammation markers; X-ray crystallography of KLK5-Fab complex\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional validation in multiple mouse disease models; bispecific antibody demonstrates joint KLK5/7 role; allosteric mechanism structurally defined\",\n      \"pmids\": [\"36516271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KLK7 expression in keratinocytes is regulated by TNF signaling; inhibition of KLK7 expression decreases proinflammatory responses to TNF in keratinocytes, placing KLK7 downstream of TNF in psoriatic inflammation.\",\n      \"method\": \"KLK7 siRNA knockdown in keratinocytes; TNF stimulation assays; measurement of proinflammatory cytokine responses; pharmacogenetic study with functional validation\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with defined inflammatory phenotype; mechanistic link to TNF pathway established functionally; single lab\",\n      \"pmids\": [\"37672660\"],\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), leading to loss of enzymatic activity; KLK7 cleaves and inactivates mast cell chymase; KLK7 hydrolyzes multiple cytokines including IFN-α, IFN-β, IFN-γ, IL-28A/IFN-λ2, IL-20, IL-22, and IL-27 (predominantly interferon and IL-10 families).\",\n      \"method\": \"Protease-specific inhibitors; active-site variants; in vitro cleavage assays; protein BLAST for substrate identification; activity measurements post-cleavage\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with inhibitors and active-site variants identifying autolysis sites and novel substrates including cytokines and mast cell proteases\",\n      \"pmids\": [\"39655764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK5 and KLK7 drive HPV-dependent cervical carcinogenesis; their absence ameliorates the HPV phenotype through modulation of KLK14 activation; KLK14 then activates PAR-2-dependent RhoA and NF-κB signaling pathways to exert pro-tumorigenic effects, placing KLK7 upstream of KLK14 activation in a protease cascade governing cervical carcinogenesis.\",\n      \"method\": \"Genetically engineered mice (KLK5/KLK7 double knockout); bulk RNA-seq; reporter assays for RhoA and NF-κB; human cervical biopsy expression analysis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in mouse model with pathway reporter assays; single lab\",\n      \"pmids\": [\"40753921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK7 in macrophages promotes inflammatory macrophage polarization and migration in visceral adipose tissue during obesity; macrophage-specific KLK7 knockout (KLK7MKO) reduces pro-inflammatory gene expression, restricts macrophage migration by increasing cell adhesion, and decreases immune cell infiltration into epididymal adipose tissue of HFD-fed mice.\",\n      \"method\": \"Macrophage-specific conditional KLK7 knockout (Cre-lox); HFD mouse model; flow cytometry for macrophage subsets; inflammatory gene expression analysis; cell adhesion assays; correlation with human visceral adipose tissue transcriptomics (n=1143)\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean cell-type-specific KO with defined mechanistic phenotype (migration, adhesion, polarization) validated in mice and correlated in large human cohort\",\n      \"pmids\": [\"40154838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK7 promotes epithelial-mesenchymal transition (EMT) in papillary thyroid cancer cells via the MAPK/ERK pathway; silencing KLK7 reduces ERK1/2 phosphorylation, suppresses EMT markers, and decreases proliferation, migration, and invasion in vitro and in vivo.\",\n      \"method\": \"KLK7 siRNA knockdown; immunohistochemistry; growth curve analysis; Western blot for ERK1/2 phosphorylation and EMT markers; nude mouse xenograft model\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with defined pathway (MAPK/ERK) and EMT phenotype in vitro and in vivo; single lab\",\n      \"pmids\": [\"39991575\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"KLK7 overexpression in colorectal cancer cells enhances peritoneal dissemination in vivo; in vitro, it increases proliferation, migration, spheroid formation, adhesion to ECM proteins, and upregulates moesin (MSN) and integrin subunits, indicating cytoskeletal remodeling and altered matrix interactions.\",\n      \"method\": \"Stable KLK7 overexpression; xenograft peritoneal metastasis mouse model; Peritoneal Cancer Index scoring; in vitro migration, adhesion, spheroid assays; gene expression analysis\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain-of-function in vivo and in vitro with specific molecular targets identified (moesin, integrins); single lab\",\n      \"pmids\": [\"41335524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NMDA receptor signaling in astrocytes negatively regulates KLK7 mRNA expression through NF-κB; inhibition of NF-κB signaling increases KLK7 expression in astrocytes and promotes degradation of amyloid-β (Aβ), identifying KLK7 as an astrocyte-derived Aβ-degrading protease; in vivo NF-κB inhibitor injection upregulates Klk7 and reduces Aβ levels.\",\n      \"method\": \"NMDA receptor antagonist (memantine) and NF-κB inhibitor treatment of astrocytes; KLK7 expression analysis; Aβ degradation assays; in vivo mouse model with NF-κB inhibitor injection and Aβ measurement\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — identifies novel KLK7 substrate (Aβ) and upstream regulatory pathway with in vivo validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of store-operated Ca2+ entry (SOCE) via Stim1/2 knockout in mouse epidermis leads to elevated Klk7 levels and increased chymotrypsin-like serine protease activity, accompanied by alterations in desmoglein 1 and hyperkeratosis; this places SOCE/Ca2+ signaling upstream of KLK7 activity in epidermal barrier maintenance.\",\n      \"method\": \"Epithelial-specific Stim1/2 conditional knockout mice; RNA-seq; transepidermal water loss measurement; in situ protease activity assays; immunofluorescence for Dsg1\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined phenotype linking Ca2+ signaling to KLK7 activity; preprint, not peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Substrate-analog and non-peptide inhibitors of KLK7 with Ki values <100 nM were developed; a key determinant of inhibitor selectivity is alanine at position 190 in the S1 pocket. KLK7 inhibition blocks chemokine cleavage and moesin gene upregulation by KLK7, confirming these as functional downstream activities; mutating T190A in murine Klk7 restored human-inhibitor potency, validating a species-adapted model.\",\n      \"method\": \"Medicinal chemistry synthesis; Ki measurement; KLK7 crystal structure-guided design; site-directed mutagenesis (T190A); cell-based assays for chemokine cleavage and moesin upregulation; ovarian cancer xenograft mouse model\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structure-guided mutagenesis with Ki determination and functional cell-based validation; identifies structural basis of S1 pocket selectivity\",\n      \"pmids\": [\"41855304\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLK7 is a chymotrypsin-like serine protease secreted from lamellar granules in the stratum corneum (regulated by LEKTI/SPINK5 in a pH-dependent manner and transcriptionally by the IL-13–ERK–EGR1 and TNF signaling axes) that drives desquamation by directly cleaving corneodesmosomal proteins CDSN and DSC1 (and DSG1 after KLK5-mediated activation of its proform); beyond skin, KLK7 cleaves cytokines (IFNs, IL-10 family members), mast cell chymase, ECM proteins (via pro-MMP10 activation, IGFBP6/thrombospondin-1 cleavage), and amyloid-β in astrocytes, and promotes inflammation and tumor progression through integrin downregulation, MAPK/ERK-driven EMT, PAR-2/RhoA/NF-κB signaling (via KLK14 activation), and macrophage polarization/migration in adipose tissue.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KLK7 is a secreted chymotrypsin-like serine protease that plays a central role in epidermal desquamation and contributes to extracellular matrix remodeling, inflammation, and cancer progression. In the epidermis, KLK7 is activated from its proform by KLK5 and directly cleaves corneodesmosome components corneodesmosin and desmocollin 1 at acidic pH, with its activity tightly regulated by the pH-dependent inhibitor LEKTI (SPINK5) and spatial segregation within lamellar granules; dysregulation of this proteolytic cascade underlies barrier defects in Netherton syndrome and atopic dermatitis [PMID:15140227, PMID:17596512, PMID:15675955, PMID:27769847]. Beyond the skin, KLK7 cleaves ECM-associated substrates including MMP2, pro-MMP10, IGFBP3, and thrombospondin 1, promotes epithelial-mesenchymal transition via MAPK/ERK signaling in cancer cells, and drives pro-inflammatory macrophage polarization and immune cell infiltration in adipose tissue [PMID:30705123, PMID:39991575, PMID:28932870, PMID:40154838]. KLK7 transcription is induced by IL-13 through ERK1/2-dependent activation of EGR-1, which binds directly to the KLK7 promoter, and the enzyme also hydrolyzes multiple cytokines including interferons and interleukins, linking it to innate immune regulation [PMID:33276948, PMID:39655764].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that KLK7 encodes a chymotryptic serine protease with broad tissue expression and hormonal regulation placed it within the kallikrein gene cluster and suggested roles beyond the skin.\",\n      \"evidence\": \"Genomic characterization, RT-PCR tissue profiling, and estrogen/glucocorticoid treatment of BT-474 breast cancer cells\",\n      \"pmids\": [\"10974542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hormonal regulation shown only in a single breast cancer cell line\", \"Endogenous substrates not yet identified\", \"Functional significance outside skin unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of corneodesmosin and desmocollin 1 as direct KLK7 substrates, together with the demonstration that KLK5 activates pro-KLK7, established a proteolytic cascade model for desquamation.\",\n      \"evidence\": \"In vitro cleavage assays with recombinant and epidermal substrates at acidic pH, including deglycosylated CDSN\",\n      \"pmids\": [\"15140227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of the KLK5→KLK7 cascade not yet performed\", \"Regulation of cascade termination undefined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Spatial segregation of KLK7 from its inhibitor LEKTI within lamellar granules, and the barrier defect in LEKTI-deficient Netherton syndrome skin, resolved how premature corneodesmosome degradation is prevented in normal epidermis.\",\n      \"evidence\": \"Immunoelectron microscopy and confocal microscopy of normal and Netherton syndrome skin\",\n      \"pmids\": [\"15675955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of differential sorting of KLK7 versus LEKTI into lamellar granules not defined\", \"Relative contributions of KLK7 versus KLK5 to Netherton pathology not separated\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that LEKTI inhibits KLK7 in a pH-dependent manner—releasing active protease at acidic pH—provided the molecular basis for how the epidermal pH gradient controls desquamation.\",\n      \"evidence\": \"Kinetic inhibition assays and pH-shift release experiments with LEKTI fragments\",\n      \"pmids\": [\"17596512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo pH measurement at the LEKTI-KLK7 interface not achieved\", \"Contribution of other endogenous inhibitors not assessed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"In atopic dermatitis, impaired KLK7 secretion from lamellar granules despite elevated protein levels explained the paradox of compact hyperkeratosis coexisting with high KLK7 expression.\",\n      \"evidence\": \"In situ zymography of tape-stripped corneocytes, western blot of stratum corneum, immunostaining, and electron microscopy of AD skin\",\n      \"pmids\": [\"27769847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of impaired KLK7 secretion in AD not identified\", \"Causal versus consequential role of the secretion defect not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defining KLK7's chymotryptic cleavage specificity at the proteome level and showing that the S195A single mutant retains residual activity refined understanding of its catalytic mechanism.\",\n      \"evidence\": \"PICS mass spectrometry with human peptide libraries and active-site mutagenesis kinetics\",\n      \"pmids\": [\"28754951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for residual S195A activity not resolved\", \"Extended substrate specificity beyond peptide libraries not captured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Adipose-specific Klk7 knockout revealing reduced weight gain, improved insulin sensitivity, and anti-inflammatory macrophage polarization established KLK7 as a regulator of metabolic inflammation beyond its epidermal role.\",\n      \"evidence\": \"Conditional adipose-specific Klk7 knockout mice on high-fat diet with metabolic phenotyping and macrophage analysis\",\n      \"pmids\": [\"28932870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct KLK7 substrates in adipose tissue unknown\", \"Mechanism linking KLK7 to macrophage polarization undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Quantitative degradomics identified MMP2, IGFBP3, pro-MMP10, and thrombospondin 1 as KLK7 substrates in cancer cell secretomes, positioning KLK7 as a multifunctional ECM remodeling protease in ovarian cancer.\",\n      \"evidence\": \"PROTOMAP-SILAC and TAILS quantitative proteomics in SKOV-3 and OVMZ-6 secretomes with biochemical validation\",\n      \"pmids\": [\"30705123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of each substrate cleavage on tumor biology not individually tested\", \"In vivo relevance in ovarian cancer models not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that IL-13 induces KLK7 transcription through ERK1/2→EGR-1 binding to the KLK7 promoter linked Th2 cytokine signaling to KLK7 upregulation in atopic dermatitis.\",\n      \"evidence\": \"Luciferase reporter with EBS mutant, ChIP, EGR1 shRNA knockdown, and Egr1 knockout mice with DNCB-induced AD\",\n      \"pmids\": [\"33276948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other Th2 cytokines use the same transcriptional axis unknown\", \"Contribution of EGR-1-driven KLK7 to barrier dysfunction versus inflammation not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Inhibitory antibodies against KLK7 and KLK5 that protect in Netherton syndrome and atopic dermatitis mouse models validated these proteases as therapeutic targets and revealed allosteric inhibition as a viable strategy.\",\n      \"evidence\": \"Mouse models of NS and AD treated with mono- and bispecific inhibitory antibodies; KLK5-Fab crystal structure\",\n      \"pmids\": [\"36516271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of KLK7 bound to its inhibitory antibody not yet solved\", \"Human clinical translation not demonstrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"KLK7 autolysis at two loop sites and its capacity to cleave mast cell chymase and multiple interferons/interleukins expanded its substrate repertoire to innate immune mediators and revealed a self-regulatory inactivation mechanism.\",\n      \"evidence\": \"In vitro cleavage assays with active-site variants, protease-specific inhibitors, and recombinant cytokines\",\n      \"pmids\": [\"39655764\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biological relevance of cytokine cleavage and chymase inactivation not validated in vivo\", \"Kinetic parameters for cytokine cleavage not provided\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Macrophage-specific KLK7 knockout reduced pro-inflammatory polarization and macrophage infiltration into obese adipose tissue, establishing a cell-autonomous role for KLK7 in macrophage inflammatory function.\",\n      \"evidence\": \"Macrophage-specific KLK7 conditional knockout mice on HFD; adhesion, migration assays; inflammatory gene quantification\",\n      \"pmids\": [\"40154838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrates of KLK7 in macrophages remain unidentified\", \"Whether KLK7 acts intracellularly or after secretion in macrophages is unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"KLK7 promotes EMT and invasion in papillary thyroid cancer through MAPK/ERK signaling, extending its oncogenic role to a new cancer type with a defined pathway mechanism.\",\n      \"evidence\": \"KLK7 knockdown in PTC cell lines, phospho-ERK western blot, EMT marker profiling, and nude mouse xenograft\",\n      \"pmids\": [\"39991575\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which KLK7 activates ERK signaling is unknown\", \"KLK7 substrates mediating EMT not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of KLK7's direct substrates in adipose tissue and macrophages, the structural basis for its allosteric inhibition, and whether its cytokine-processing and amyloid-β-degrading activities are physiologically relevant.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of KLK7 in complex with an inhibitor or substrate\", \"Adipose and macrophage substrates entirely unknown\", \"Amyloid-β degradation shown only in preprint without peer review\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 5, 8]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 15]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KLK5\",\n      \"LEKTI\",\n      \"CDSN\",\n      \"DSC1\",\n      \"EGR1\",\n      \"MMP2\",\n      \"MMP10\",\n      \"THBS1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"KLK7 is a secreted chymotrypsin-like serine protease that functions as a central effector of epidermal desquamation and participates in extracellular proteolytic cascades in multiple tissues. In the stratum corneum, KLK7 is released from lamellar granules and directly cleaves the corneodesmosomal proteins corneodesmosin (CDSN) and desmocollin 1 (DSC1), with its activity gated by pH-dependent inhibition by LEKTI/SPINK5 fragments and by upstream activation of its proform by KLK5 [PMID:15140227, PMID:17596512, PMID:15675955]. Beyond skin barrier homeostasis, KLK7 cleaves interferons, IL-10-family cytokines, mast cell chymase, IGFBP6, thrombospondin-1, and pro-MMP10, and its transcription is regulated by IL-13–ERK–EGR1, TNF, and NF-κB signaling axes [PMID:39655764, PMID:30705123, PMID:33276948, PMID:37672660]. In disease contexts, KLK7 promotes inflammatory macrophage polarization and migration in adipose tissue, drives MAPK/ERK-dependent epithelial–mesenchymal transition in cancer, and participates in a KLK5/KLK7→KLK14→PAR-2/NF-κB protease cascade in cervical carcinogenesis [PMID:40154838, PMID:39991575, PMID:40753921].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of KLK7 (SCCE) as a chymotrypsin-like serine protease of the stratum corneum established the molecular identity of the desquamation enzyme and placed it in a kallikrein gene cluster on 19q13.\",\n      \"evidence\": \"cDNA cloning and sequence homology analysis from human stratum corneum\",\n      \"pmids\": [\"8898378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no substrates identified\", \"no in vitro enzymatic characterization\", \"regulation unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Reconstituted cleavage assays resolved which corneodesmosomal targets KLK7 acts on directly (CDSN, DSC1 but not DSG1) and showed that KLK5 activates pro-KLK7, establishing a protease activation cascade driving desquamation.\",\n      \"evidence\": \"In vitro cleavage assays with recombinant and epidermal substrates at acidic pH; proform activation assays\",\n      \"pmids\": [\"15140227\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"in vivo confirmation of sequential activation not yet shown\", \"cleavage site mapping not performed in this study\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Subcellular imaging revealed that KLK7 resides in lamellar granules and is secreted after LEKTI, explaining how premature desquamation is prevented and why LEKTI loss (Netherton syndrome) leads to barrier failure.\",\n      \"evidence\": \"Confocal and immunoelectron microscopy of normal and Netherton syndrome skin biopsies\",\n      \"pmids\": [\"15675955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism of secretion timing not defined\", \"whether impaired secretion occurs in diseases other than Netherton syndrome unknown at this point\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Kinetic characterization of LEKTI fragment–KLK interactions revealed pH-dependent release of active KLK5 (and differential inhibition of KLK7 and KLK14), providing the molecular gating mechanism that couples skin acidification to desquamation.\",\n      \"evidence\": \"Biochemical inhibition kinetics and pH-dependent binding/release assays with furin-processed LEKTI fragments\",\n      \"pmids\": [\"17596512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"which specific LEKTI fragments are the dominant KLK7 inhibitors in vivo remains unclear\", \"structural basis of pH-dependent release not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Comprehensive substrate-site profiling defined KLK7's chymotryptic specificity (hydrophobic P2-P1, hydrophilic P1'-P2') and showed that the canonical S195A active-site mutant retains residual activity, requiring a double catalytic-triad mutation for true inactivation.\",\n      \"evidence\": \"PICS mass spectrometry-based cleavage profiling; kinetic characterization of wild-type and active-site mutants\",\n      \"pmids\": [\"28754951\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"extended subsite cooperativity not fully modeled\", \"no crystal structure of KLK7 with a substrate analog at this time\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Adipose-tissue-specific Klk7 knockout demonstrated a non-skin role: KLK7 promotes weight gain, insulin resistance, and pro-inflammatory macrophage polarization under high-fat diet, establishing KLK7 as a metabolic regulator.\",\n      \"evidence\": \"Conditional Cre-lox KO in mouse adipose tissue with metabolic phenotyping and macrophage flow cytometry\",\n      \"pmids\": [\"28932870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct adipose substrates of KLK7 not identified\", \"mechanism linking protease activity to macrophage polarization unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Quantitative degradomics expanded the KLK7 substrate repertoire beyond corneodesmosomes to ECM remodeling mediators (pro-MMP10 activation, IGFBP6, thrombospondin-1 cleavage) in ovarian cancer secretomes, linking KLK7 to invasion and matrix turnover.\",\n      \"evidence\": \"qPROTOMAP and TAILS quantitative proteomics in OVMZ6 and SKOV3 ovarian cancer cells with biochemical validation\",\n      \"pmids\": [\"30705123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"in vivo relevance of each novel substrate not confirmed\", \"catalytic efficiency for individual substrates not fully quantified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of the IL-13–ERK1/2–EGR1 transcriptional axis controlling KLK7 promoter activity explained how Th2 inflammation upregulates KLK7 in atopic dermatitis skin.\",\n      \"evidence\": \"Promoter-reporter assay with EBS point mutation, EGR1 knockdown, Egr1 KO mouse AD model, ERK inhibitor epistasis in keratinocytes\",\n      \"pmids\": [\"33276948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"whether other Th2 cytokines (IL-4, IL-31) use the same promoter element is unknown\", \"chromatin-level regulation not examined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Therapeutic proof-of-concept was achieved with inhibitory anti-KLK5/KLK7 bispecific antibodies that restored skin barrier integrity and reduced inflammation in Netherton syndrome and AD mouse models, confirming KLK5 and KLK7 as co-drivers of skin inflammatory disease.\",\n      \"evidence\": \"Antibody engineering; mouse NS and AD models; X-ray crystallography of KLK5–Fab complex revealing allosteric inhibition\",\n      \"pmids\": [\"36516271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of antibody–KLK7 interaction not resolved (only KLK5–Fab crystallized)\", \"human clinical efficacy unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery of KLK7-mediated hydrolysis of interferons (IFN-α, -β, -γ), IL-10-family cytokines, and mast cell chymase broadened KLK7's functional scope to immune modulation and revealed that KLK7 undergoes autolytic inactivation at two specific loops.\",\n      \"evidence\": \"In vitro cleavage assays with active-site variants and protease-specific inhibitors; substrate identification by protein BLAST\",\n      \"pmids\": [\"39655764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"physiological relevance of cytokine cleavage in vivo not demonstrated\", \"whether autolysis is a regulatory mechanism or artifact at high concentrations not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple 2025 studies extended KLK7's disease roles: a KLK5/KLK7→KLK14→PAR-2/NF-κB cascade drives HPV-dependent cervical carcinogenesis, macrophage-specific KLK7 promotes inflammatory polarization/migration in obese adipose tissue, KLK7 drives MAPK/ERK-dependent EMT in thyroid cancer, and KLK7 overexpression enhances peritoneal dissemination in colorectal cancer.\",\n      \"evidence\": \"KLK5/KLK7 double-KO mice with RNA-seq and pathway reporters; macrophage-specific Klk7 KO with HFD; KLK7 siRNA with ERK/EMT readouts in thyroid cancer; KLK7 overexpression xenograft peritoneal metastasis model\",\n      \"pmids\": [\"40753921\", \"40154838\", \"39991575\", \"41335524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct KLK7 substrates mediating EMT, macrophage migration, and peritoneal dissemination not individually identified\", \"KLK7 versus KLK5 individual contributions hard to deconvolute in double-KO cervical cancer model\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Structure-guided development of potent (<100 nM) KLK7 inhibitors identified Ala190 in the S1 pocket as the key selectivity determinant and confirmed chemokine cleavage and moesin upregulation as functional downstream outputs of KLK7 catalytic activity.\",\n      \"evidence\": \"Medicinal chemistry; Ki measurement; T190A mutagenesis restoring inhibitor potency in murine Klk7; cell-based chemokine and moesin assays; ovarian cancer xenograft\",\n      \"pmids\": [\"41855304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no co-crystal structure of KLK7 with the inhibitor reported\", \"in vivo pharmacokinetics and therapeutic window not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of direct KLK7 substrates mediating its pro-tumorigenic and metabolic effects, the physiological significance of cytokine and amyloid-β cleavage in vivo, structural characterization of KLK7–inhibitor and KLK7–antibody complexes, and the relative contributions of KLK7 versus other kallikreins in protease cascades across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no KLK7 crystal structure with a bound substrate or therapeutic antibody\", \"in vivo substrate validation in non-skin contexts largely absent\", \"whether autolysis is physiologically regulated remains unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5, 6, 12, 13, 19, 26]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 3, 12, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 13, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [13, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 20, 22]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 6, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KLK5\",\n      \"SPINK5\",\n      \"CDSN\",\n      \"DSC1\",\n      \"DSG1\",\n      \"KLK14\",\n      \"MMP10\",\n      \"EGR1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}