{"gene":"SERPINB3","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":1998,"finding":"Recombinant SERPINB3 (SCCA1) inhibits chymotrypsin and cathepsin L in vitro, establishing it as an inhibitory-type serpin targeting cysteine and serine proteases.","method":"In vitro protease inhibition assay with recombinant protein","journal":"Tumour biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay with recombinant protein, replicated across multiple studies in the corpus","pmids":["9817978"],"is_preprint":false},{"year":2001,"finding":"SERPINB3 (SCCA1) suppresses NK cell migration induced by monocyte chemoattractant protein-1 in vitro, and this antichemotactic effect is abrogated by mutation of the reactive site loop, demonstrating that the anti-protease activity is required.","method":"NK cell migration assay with recombinant SCCA1 and reactive-site loop mutant","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro functional assay with mutagenesis establishing mechanistic requirement of the reactive site loop; single lab but two orthogonal methods (migration assay + mutagenesis)","pmids":["11280721"],"is_preprint":false},{"year":2001,"finding":"Antisense suppression of SCCA (SERPINB3) in SCC tumor cells in vivo leads to increased apoptosis and NK cell infiltration, reducing tumor growth in nude mice.","method":"Antisense retroviral knockdown in vivo + immunohistochemistry of tumor tissue","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined cellular phenotypes (apoptosis and NK infiltration); single lab","pmids":["11280721"],"is_preprint":false},{"year":2010,"finding":"SERPINB3 expression in HepG2 cells induces epithelial-mesenchymal transition (EMT), evidenced by decreased E-cadherin, increased β-catenin and vimentin, loss of desmosomes, and increased cell migration, invasion, and anchorage-independent growth. These effects occur at both autocrine and paracrine levels and are independent of the anti-protease activity of the protein (active-loop deleted mutant retains scatter activity).","method":"Stable transfection of SERPINB3 in HepG2 cells; exogenous recombinant protein addition to HepG2/MDCK cells; active-loop deleted mutant; wound healing/invasion assays; ultrastructural analysis","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transfection, exogenous protein, loss-of-function mutant, invasion assays, ultrastructure); replicated paracrine and autocrine models in single rigorous study","pmids":["20527027"],"is_preprint":false},{"year":2010,"finding":"SERPINB3 upregulates TGF-β1 mRNA and protein in transfected hepatocytes (primary human hepatocytes, HepG2, Huh7), and the integrity of the reactive site loop is required for this effect.","method":"Transfection of intact SERPINB3 or reactive-site loop deleted mutants; qRT-PCR and immunoassay for TGF-β1; correlation in liver biopsies","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of reactive site loop identifies mechanistic requirement; multiple cell lines tested; single lab","pmids":["20212457"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of wild-type SERPINB3 resolved at 2.7 Å, and molecular modelling revealed that the SCCA-PD polymorphic variant (Gly351Ala in reactive center loop) has increased hydrophobic profile, conferring greater cathepsin L and papain inhibitory activity and higher JNK1 inhibitory effect compared to wild-type.","method":"X-ray crystallography; in vitro kinetic analysis with recombinant proteins; JNK activity assay; 3D homology modelling","journal":"Experimental biology and medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus in vitro kinetic assay with mutagenesis-equivalent polymorphic variant; single lab but multiple orthogonal methods","pmids":["21383048"],"is_preprint":false},{"year":2014,"finding":"SERPINB3 is transcriptionally upregulated by oncogenic Ras via the MAPK pathway and the ETS family transcription factor PEA3. Increased SERPINB3 expression leads to inhibition of protein turnover, induction of the unfolded protein response (UPR), and NF-κB activation, which are essential for Ras-mediated cytokine production (e.g., IL-6) and tumor growth.","method":"Transcriptional reporter assays; genetic knockdown/overexpression; NF-κB and UPR pathway biochemical assays; mouse tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (reporter assays, KD/OE, pathway assays, in vivo models) in single study; confirmed in human tumor specimens","pmids":["24759783"],"is_preprint":false},{"year":2014,"finding":"SERPINB3 (SCCA1) overexpression in mammary epithelial cells promotes oncogenic transformation and EMT, and induces a prolonged non-lethal UPR that activates NF-κB and IL-6 autocrine signaling to drive pro-tumorigenic inflammation.","method":"Stable overexpression and siRNA knockdown; UPR and NF-κB reporter assays; IL-6 ELISA; mouse mammary tumor model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain/loss-of-function, multiple pathway readouts, in vivo confirmation; independent replication of UPR/NF-κB mechanism across two labs (PMID 24759783)","pmids":["25213322"],"is_preprint":false},{"year":2014,"finding":"SERPINB3 localizes to mitochondrial inner compartments (fraction increases under oxidative stress) and protects hepatoma cells from doxorubicin/cisplatin-induced death by inhibiting mitochondrial respiratory Complex I, thereby reducing ROS generation and preventing mitochondrial permeability transition pore opening.","method":"Subcellular fractionation; mitochondrial ROS measurement; PTP opening assays; cell viability assays with pro-oxidant chemotherapeutics; co-immunoprecipitation with Complex I","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct fractionation plus functional assays (ROS, PTP, cell viability) linking mitochondrial localization to mechanism; single lab, multiple orthogonal methods","pmids":["24810714"],"is_preprint":false},{"year":2015,"finding":"SERPINB3 upregulates Myc through two mechanisms in hepatoma cells and transgenic mice: (1) direct inhibition of calpain protease activity, preventing calpain-mediated cleavage of Myc into its non-oncogenic cytoplasmic form (Myc-nick); (2) indirect activation of the Yap/Hippo pathway, which transcriptionally increases Myc. Recombinant SerpinB3 inhibits calpain activity in vitro.","method":"Transgenic mouse overexpression; hepatoma cell transfection; in vitro calpain inhibition assay; Yap pathway analysis; co-IP; Western blot","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic assay (calpain inhibition) plus pathway epistasis (Yap/Hippo) and in vivo transgenic model; single lab, multiple orthogonal methods","pmids":["26634820"],"is_preprint":false},{"year":2015,"finding":"Hypoxia up-regulates SERPINB3 transcription, protein synthesis and extracellular release in liver cancer cells specifically through HIF-2α (not HIF-1α) binding to the SERPINB3 promoter, in a redox-sensitive manner requiring intracellular ROS generation.","method":"ChIP assay; siRNA silencing of HIF-1α and HIF-2α; ROS measurement; qRT-PCR and Western blot; hypoxia exposure experiments","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP directly demonstrates HIF-2α binding to promoter; siRNA epistasis distinguishes HIF-1α vs HIF-2α; single lab, multiple orthogonal methods","pmids":["25544768"],"is_preprint":false},{"year":2017,"finding":"Exogenous recombinant SerpinB3 added to activated hepatic stellate cells (HSC/MFs and LX2) upregulates pro-fibrogenic gene expression and promotes oriented migration but not proliferation. In transgenic mice overexpressing SerpinB3 in hepatocytes, chronic liver injury leads to increased fibrogenic gene expression, collagen deposition, and αSMA-positive HSC/MFs, confirming paracrine pro-fibrogenic activity.","method":"Recombinant protein addition to primary HSC/MF cultures and LX2 cells; transgenic mouse models (CCl4 and MCD diet); qRT-PCR; immunohistochemistry","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro gain-of-function with recombinant protein confirmed in two independent in vivo mouse models; single lab","pmids":["28611447"],"is_preprint":false},{"year":2019,"finding":"MiR-122 directly targets the SERPINB3 mRNA 3'UTR as demonstrated by luciferase assay; miR-122 transfection decreased SERPINB3 mRNA and protein, while miR-122 inhibition increased SERPINB3 expression. Overexpression of SERPINB3 blunted the sensitizing effect of miR-122 on sorafenib treatment.","method":"Luciferase reporter assay; miR-122 transfection/inhibition; Western blot; cell viability assay","journal":"Journal of clinical medicine","confidence":"High","confidence_rationale":"Tier 1 / Moderate — luciferase assay directly demonstrates miR-122/SERPINB3 mRNA interaction; single lab, multiple validation methods","pmids":["30717317"],"is_preprint":false},{"year":2022,"finding":"SERPINB3 inhibits cathepsin L and protects cervical cancer cells from radiation-induced lysoptosis (lysosomal cell death). Genetic knockout of SERPINB3 sensitizes cells to radiation-induced necrotic death; rescue with wild-type SERPINB3 but not a reactive site loop mutant restores protection, demonstrating that protease inhibitory activity is required.","method":"CRISPR/genetic knockout; wild-type vs. reactive-site loop mutant rescue; cell death assays (necrosis, apoptosis markers); cathepsin L genetic knockdown; transcriptomics","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis establishes mechanistic requirement of inhibitory activity; KO + rescue design; cathepsin L identified as downstream effector by genetic KD; single lab, multiple orthogonal methods","pmids":["35022555"],"is_preprint":false},{"year":2022,"finding":"SERPINB3 suppresses antitumor immunity by promoting STAT-dependent expression of chemokines CXCL1/CXCL8 and alarmins S100A8/S100A9, which recruit monocytes and myeloid-derived suppressor cells (MDSCs), thereby inhibiting cytotoxic T cell function. Inhibition of STAT activation by ruxolitinib or siRNA abrogates CXCL1/8 and S100A8/A9 expression in SERPINB3-expressing cells.","method":"SERPINB3 overexpression/knockdown; STAT inhibitor (ruxolitinib); STAT siRNA; monocyte/MDSC migration assays; mouse tumor models; flow cytometry of immune infiltrates","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis via STAT inhibition/siRNA places SERPINB3 upstream of STAT; in vivo KD confirms immune phenotype; multiple orthogonal methods; single lab","pmids":["37279067"],"is_preprint":false},{"year":2022,"finding":"SerpinB3 is essential for glioblastoma cancer stem cell (CSC) survival and maintenance by buffering cathepsin L-mediated lysosomal cell death; knockdown of SerpinB3 increases cathepsin L-dependent apoptosis and radiosensitivity in CSCs.","method":"Genetic depletion (shRNA/siRNA); cathepsin L activity/apoptosis assays; CSC sphere formation; mouse xenograft models; radiation sensitivity assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (cathepsin L-mediated death); in vivo xenograft confirmation; single lab, multiple orthogonal methods","pmids":["36103817"],"is_preprint":false},{"year":2023,"finding":"SERPINB3 inhibits the cysteine protease calpain, a key enzyme in the MYC degradation pathway, thereby stabilizing MYC and driving metabolic reprogramming (heightened carnitine/acylcarnitine and amino acid metabolism) and the basal-like/squamous subtype in pancreatic cancer. SERPINB3 transgene expression enhances invasion in vitro and promotes lung metastasis in a xenograft model.","method":"SERPINB3 transgene expression; in vitro invasion assays; mouse xenograft model; calpain activity assays; metabolome analyses","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — calpain inhibition assay mechanistically links SERPINB3 to MYC stabilization; in vivo confirmation; metabolomics provides orthogonal evidence; replicates and extends findings from PMID 26634820","pmids":["37980563"],"is_preprint":false},{"year":2022,"finding":"SERPINB3 downregulation (by HPV-E6/E7) reduces USP1-mediated deubiquitination of FANCD2-FANCI in the Fanconi anemia DNA repair pathway, thereby impairing cisplatin-induced DNA interstrand crosslink repair and increasing HNSCC cell apoptosis.","method":"SERPINB3 siRNA knockdown; FANCD2-FANCI ubiquitination assays; DNA damage repair assays; patient-derived xenograft model with nanoparticle siRNA delivery","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical pathway assay (ubiquitination of FANCD2-FANCI) links SERPINB3 KD to FA pathway; in vivo PDX confirmation; single lab","pmids":["36382555"],"is_preprint":false},{"year":2014,"finding":"SERPINB3 is expressed on the surface of CD27+ B lymphocytes in healthy individuals; this surface expression is reduced in HCV-infected patients and absent in SLE patients.","method":"Flow cytometry; confocal microscopy; correlation with CD27 expression","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization by flow cytometry and confocal; single lab, no functional consequence established","pmids":["22829702"],"is_preprint":false},{"year":2014,"finding":"SERPINB3 is expressed in hepatic progenitor cells (EpCAM+ sorted cells from fetal and adult livers, CK-7/CK-19/EpCAM/CD-90 positive cells in cirrhotic livers); in a mouse model of liver injury, SerpinB3 expression progressively increases while activated caspase-3 decreases, consistent with an anti-apoptotic role in progenitor cells.","method":"Cell sorting; immunohistochemistry; RT-PCR with sequencing; mouse injury model (LPS/D-galactosamine)","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by cell sorting and IHC with functional correlate (inverse caspase-3); multiple methods; single lab","pmids":["24517394"],"is_preprint":false},{"year":2014,"finding":"SERPINB3 attenuates cytochrome c release from mitochondria, contributing to apoptosis resistance. This was documented in vitro and in vivo across multiple studies.","method":"Cytochrome c release assay; transfection; in vitro apoptosis induction","journal":"Autoimmunity reviews / Annals of hepatology (review citing in vitro and in vivo experiments)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — documented in multiple studies; mechanism further specified in PMID 24810714 (Complex I inhibition preventing ROS/PTP); multiple labs","pmids":["19332150","25332258"],"is_preprint":false},{"year":2014,"finding":"In atopic dermatitis, SERPINB3/B4 (mouse homolog Serpinb3a) promotes barrier dysfunction and early inflammatory responses. Serpinb3a-null mice show attenuated transepidermal water loss, reduced epidermal thickness, and reduced skin inflammation after allergen exposure. Silencing of SERPINB3/B4 in human keratinocytes decreased S100A8 expression, placing SERPINB3/B4 upstream of the S100A8-mediated inflammatory response.","method":"Serpinb3a knockout mouse; topical allergen challenge; TEWL measurement; RNA-seq; siRNA silencing in human keratinocytes","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined phenotype confirmed by human keratinocyte siRNA; RNA-seq identifies pathway; single lab, multiple orthogonal methods","pmids":["25111616"],"is_preprint":false},{"year":2020,"finding":"TEAD4 transcriptionally regulates SERPINB3/B4 expression in psoriatic keratinocytes, and SERPINB3/B4 mediates TEAD4-dependent chemokine secretion that promotes T cell migration.","method":"TEAD4 siRNA knockdown; SERPINB3/B4 siRNA; chemokine ELISA; T cell migration assay","journal":"Immunobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA epistasis places SERPINB3 downstream of TEAD4 and upstream of chemokine secretion; single lab, limited mechanistic detail in abstract","pmids":["32962824"],"is_preprint":false},{"year":2022,"finding":"RCL-mutagenesis of SERPINB3 scaffold can redirect its inhibitory specificity: replacing the native RCL with sequences targeting furin or TMPRSS2 generates variants that inhibit these proteases (not cathepsin L), block SARS-CoV-2 spike protein cleavage in vitro, and suppress SARS-CoV-2 replication in cells. The TMPRSS2-targeting variant (B3-TMP) shows 18-fold improvement in inhibition rate constant over alpha-1 antitrypsin.","method":"Reactive center loop mutagenesis; in vitro protease inhibition kinetic assays; pseudoparticle entry assay; live virus replication assay","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and kinetic measurements; functional cell-based validation; single lab, multiple orthogonal methods","pmids":["36293378"],"is_preprint":false},{"year":2017,"finding":"SERPINB3 induces a positive feedback loop between COX-2 and β-catenin in colorectal cancer cells; cell lines with high SerpinB3 expression show higher COX-2 and β-catenin levels, greater proliferation, and invasion compared to controls.","method":"Cell line comparison with differential SERPINB3 expression; Western blot for COX-2 and β-catenin; proliferation and invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — correlation-based in vitro evidence in cell lines; no direct KD/rescue experiment described; single lab","pmids":["28178650"],"is_preprint":false},{"year":2025,"finding":"SERPINB3 expression is transcriptionally activated by HIF1α downstream of ROS produced by TMEM65-enhanced OXPHOS in triple-negative breast cancer; SERPINB3 in turn promotes TNBC stemness, progression, and cisplatin resistance.","method":"TMEM65 knockdown/overexpression; ROS measurement; HIF1α inhibition; SERPINB3 expression analysis; cisplatin sensitivity assays; in vivo tumor models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — pathway epistasis placing SERPINB3 downstream of TMEM65/ROS/HIF1α; single lab; SERPINB3 not directly manipulated as primary subject","pmids":["40546127"],"is_preprint":false}],"current_model":"SERPINB3 is a cross-class serine/cysteine protease inhibitor that acts through its reactive center loop to inhibit cathepsin L, calpain, and other proteases, thereby blocking apoptosis (preventing cytochrome c release and lysoptosis), stabilizing MYC (by preventing calpain-mediated cleavage), activating NF-κB and IL-6 via the unfolded protein response, inhibiting NK cell chemotaxis, localizing to mitochondria to suppress Complex I-mediated ROS and permeability transition pore opening, transcriptionally responding to oncogenic Ras (via MAPK/PEA3) and hypoxia (via HIF-2α/ROS), and promoting EMT, pro-fibrogenic signaling, and immune evasion through STAT-dependent chemokine production."},"narrative":{"mechanistic_narrative":"SERPINB3 is an inhibitory-type serpin that uses its reactive center loop (RCL) to inhibit cysteine and serine proteases — including cathepsin L, calpain, and chymotrypsin — and thereby acts as a broad cytoprotective and pro-tumorigenic effector across epithelial cancers and tissue injury [PMID:9817978, PMID:21383048]. Many of its downstream activities are RCL-dependent: protease inhibition is required for its suppression of NK cell chemotaxis [PMID:11280721] and for protection against radiation-induced cathepsin L-mediated lysosomal cell death (lysoptosis), where genetic knockout sensitizes cells to necrotic death and only wild-type, not RCL-mutant, protein restores protection [PMID:35022555]. This cathepsin L-buffering function sustains survival of glioblastoma cancer stem cells [PMID:36103817]. By inhibiting calpain, SERPINB3 prevents cleavage of MYC into its non-oncogenic form and additionally raises MYC via Yap/Hippo activation, stabilizing MYC to drive metabolic reprogramming and aggressive squamous/basal tumor phenotypes [PMID:26634820, PMID:37980563]. SERPINB3 also drives epithelial-mesenchymal transition and pro-fibrogenic signaling through autocrine and paracrine routes — including TGF-β1 induction and activation of hepatic stellate cells — with EMT being independent of anti-protease activity but TGF-β1 induction requiring an intact RCL [PMID:20527027, PMID:20212457, PMID:28611447]. It promotes tumor-permissive inflammation and immune evasion by inducing a prolonged non-lethal unfolded protein response that activates NF-κB and IL-6 [PMID:24759783, PMID:25213322], and by driving STAT-dependent CXCL1/CXCL8 and S100A8/S100A9 production that recruits myeloid-derived suppressor cells and suppresses cytotoxic T cells [PMID:37279067]. SERPINB3 localizes to mitochondria where it inhibits respiratory Complex I to limit ROS and block permeability transition pore opening, contributing to apoptosis resistance and chemoresistance [PMID:24810714]. Its expression is induced by oncogenic Ras via MAPK/PEA3 [PMID:24759783] and by hypoxia through HIF-2α in a redox-dependent manner [PMID:25544768], and is repressed post-transcriptionally by miR-122 [PMID:30717317].","teleology":[{"year":1998,"claim":"Established the biochemical identity of SERPINB3 as a functional protease inhibitor rather than a non-inhibitory serpin, defining its core molecular activity.","evidence":"In vitro protease inhibition assays with recombinant protein against chymotrypsin and cathepsin L","pmids":["9817978"],"confidence":"High","gaps":["Full physiological substrate spectrum not defined in this assay","No cellular or in vivo context for the inhibition"]},{"year":2001,"claim":"Linked SERPINB3 protease activity to immune evasion by showing it suppresses NK cell chemotaxis in an RCL-dependent manner, and that knockdown restores apoptosis and NK infiltration in tumors.","evidence":"NK cell migration assay with RCL mutant; antisense knockdown in nude mouse SCC tumors with IHC","pmids":["11280721"],"confidence":"High","gaps":["Protease target mediating antichemotactic effect not identified","Mechanism connecting protease inhibition to migration suppression unresolved"]},{"year":2010,"claim":"Showed SERPINB3 drives EMT and pro-fibrogenic TGF-β1 signaling, separating an anti-protease-independent EMT/scatter activity from an RCL-dependent TGF-β1 induction.","evidence":"Transfection, exogenous recombinant protein, active-loop-deleted mutants, invasion/ultrastructure assays in HepG2/Huh7/hepatocytes","pmids":["20527027","20212457"],"confidence":"High","gaps":["Receptor or signaling intermediary for paracrine scatter activity unknown","How an RCL-independent activity operates mechanistically is unresolved"]},{"year":2011,"claim":"Provided structural basis for SERPINB3 inhibition and showed an RCL polymorphism (Gly351Ala) tunes cathepsin L/papain and JNK1 inhibitory potency.","evidence":"X-ray crystallography at 2.7 Å, in vitro kinetics with recombinant variants, JNK activity assay, homology modelling","pmids":["21383048"],"confidence":"High","gaps":["Functional consequence of the polymorphism in vivo not established","Mechanism of JNK inhibition not biochemically defined"]},{"year":2014,"claim":"Defined SERPINB3 as an oncogenic effector downstream of Ras/MAPK/PEA3 that sustains tumor inflammation by inducing a non-lethal UPR-driven NF-κB/IL-6 program, replicated in two independent epithelial systems.","evidence":"Reporter assays, reciprocal KD/OE, UPR/NF-κB pathway readouts, IL-6 ELISA, mouse tumor models","pmids":["24759783","25213322"],"confidence":"High","gaps":["How protease inhibition triggers the UPR is unclear","Molecular link between SERPINB3 and proteostasis disruption undefined"]},{"year":2014,"claim":"Identified a mitochondrial localization and function for SERPINB3, where it inhibits Complex I to limit ROS and block PTP opening, providing a mechanism for chemoresistance and reduced cytochrome c release.","evidence":"Subcellular fractionation, mitochondrial ROS and PTP assays, co-IP with Complex I, viability assays with pro-oxidant drugs","pmids":["24810714","19332150","25332258"],"confidence":"High","gaps":["How a serpin reaches the mitochondrial inner compartment is unknown","Direct Complex I subunit target not mapped"]},{"year":2015,"claim":"Established calpain inhibition as a route by which SERPINB3 stabilizes MYC, complemented by Yap/Hippo-mediated transcriptional MYC upregulation.","evidence":"In vitro calpain inhibition assay, hepatoma transfection, transgenic mice, Yap pathway analysis, co-IP","pmids":["26634820"],"confidence":"High","gaps":["Mechanism linking SERPINB3 to Yap activation not resolved","Relative contribution of the two MYC mechanisms unquantified"]},{"year":2015,"claim":"Placed SERPINB3 in hypoxic signaling, showing HIF-2α (not HIF-1α) drives its transcription and extracellular release in a ROS-dependent manner.","evidence":"ChIP, HIF-1α/HIF-2α siRNA, ROS measurement, qRT-PCR/Western under hypoxia","pmids":["25544768"],"confidence":"High","gaps":["Source of the redox signal selecting HIF-2α not defined","Function of secreted SERPINB3 in the hypoxic niche unclear"]},{"year":2017,"claim":"Confirmed paracrine pro-fibrogenic activity, showing recombinant SERPINB3 activates hepatic stellate cells and hepatocyte-overexpressing mice develop more fibrosis under chronic injury.","evidence":"Recombinant protein on HSC/MF and LX2 cells; CCl4 and MCD-diet transgenic mouse models; qRT-PCR/IHC","pmids":["28611447"],"confidence":"High","gaps":["Stellate-cell receptor for SERPINB3 not identified","Signaling pathway driving migration vs. proliferation split unresolved"]},{"year":2019,"claim":"Identified post-transcriptional control of SERPINB3 by miR-122 and linked its expression to sorafenib resistance.","evidence":"Luciferase 3'UTR reporter, miR-122 transfection/inhibition, Western blot, viability assay","pmids":["30717317"],"confidence":"High","gaps":["Physiological contexts where miR-122 regulates SERPINB3 not mapped","Mechanism of SERPINB3-driven drug resistance not specified here"]},{"year":2022,"claim":"Demonstrated that RCL-dependent cathepsin L inhibition protects against radiation-induced lysoptosis and sustains cancer stem cell survival, cementing the protease-inhibition-to-cell-death-protection axis.","evidence":"CRISPR KO with WT vs. RCL-mutant rescue, cathepsin L genetic KD, cell death assays, transcriptomics; CSC shRNA depletion with xenografts and radiosensitivity assays","pmids":["35022555","36103817"],"confidence":"High","gaps":["Trigger releasing cathepsin L to the cytosol not defined","Generality across non-irradiated lysosomal death stimuli unclear"]},{"year":2022,"claim":"Established SERPINB3 as a driver of immune evasion via STAT-dependent chemokine and alarmin production that recruits MDSCs and suppresses cytotoxic T cells.","evidence":"OE/KD, ruxolitinib and STAT siRNA, monocyte/MDSC migration, mouse tumor models, immune-infiltrate flow cytometry","pmids":["37279067"],"confidence":"High","gaps":["How SERPINB3 activates STAT signaling is not defined","Direct vs. indirect role of protease inhibition in this axis unresolved"]},{"year":2022,"claim":"Showed the SERPINB3 scaffold is RCL-programmable, generating engineered variants that inhibit furin/TMPRSS2 and block SARS-CoV-2 entry, confirming RCL identity dictates target specificity.","evidence":"RCL mutagenesis, kinetic inhibition assays, pseudoparticle entry and live-virus replication assays","pmids":["36293378"],"confidence":"High","gaps":["Native SERPINB3 does not target these proteases","In vivo antiviral utility not tested"]},{"year":2022,"claim":"Connected SERPINB3 to DNA crosslink repair, showing its HPV-driven downregulation impairs USP1-dependent FANCD2-FANCI deubiquitination and sensitizes HNSCC to cisplatin.","evidence":"siRNA KD, FANCD2-FANCI ubiquitination assays, DNA repair assays, PDX with nanoparticle siRNA","pmids":["36382555"],"confidence":"Medium","gaps":["Mechanistic link between a protease inhibitor and USP1 activity unexplained","Single-lab finding without reciprocal validation"]},{"year":2014,"claim":"Extended SERPINB3 biology beyond cancer, showing the mouse homolog promotes epidermal barrier dysfunction and S100A8-driven inflammation in atopic dermatitis.","evidence":"Serpinb3a-null mice with allergen challenge, TEWL, RNA-seq; human keratinocyte siRNA","pmids":["25111616"],"confidence":"High","gaps":["Protease target in skin inflammation not identified","Relationship between human SERPINB3 and mouse Serpinb3a function not fully reconciled"]},{"year":2025,"claim":"Placed SERPINB3 downstream of a TMEM65-OXPHOS-ROS-HIF1α axis in triple-negative breast cancer, driving stemness and cisplatin resistance.","evidence":"TMEM65 KD/OE, ROS measurement, HIF1α inhibition, SERPINB3 expression analysis, cisplatin assays, in vivo models","pmids":["40546127"],"confidence":"Medium","gaps":["SERPINB3 not directly manipulated as primary subject","Apparent HIF1α dependence contrasts with HIF-2α selectivity reported in liver cancer"]},{"year":null,"claim":"How SERPINB3 transduces protease inhibition into the broad set of downstream programs (UPR/NF-κB, STAT signaling, Yap activation, mitochondrial Complex I inhibition) at the molecular level remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying mechanism connecting cytosolic protease inhibition to nuclear/mitochondrial signaling outputs","Receptors mediating paracrine/extracellular SERPINB3 activity unidentified","How SERPINB3 localizes across cytosol, mitochondria, and cell surface is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,9,13,16,23]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,9,13,16,23]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[18]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[10,11]}],"pathway":[{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7,14,16]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,15,20]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,14,21]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,7,10]}],"complexes":[],"partners":["CTSL","CAPN","MYC","NDUFS (COMPLEX I)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P29508","full_name":"Serpin B3","aliases":["Protein T4-A","Squamous cell carcinoma antigen 1","SCCA-1"],"length_aa":390,"mass_kda":44.6,"function":"May act as a papain-like cysteine protease inhibitor to modulate the host immune response against tumor cells. 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/36581625","citation_count":12,"is_preprint":false},{"pmid":"25862847","id":"PMC_25862847","title":"Targeting mTOR and AREG with everolimus, sunitinib and sorafenib in HPV-positive and -negative SCC.","date":"2015","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/25862847","citation_count":12,"is_preprint":false},{"pmid":"26622617","id":"PMC_26622617","title":"Tumstatin induces apoptosis mediated by Fas signaling pathway in oral squamous cell carcinoma SCC-VII cells.","date":"2015","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/26622617","citation_count":12,"is_preprint":false},{"pmid":"28411387","id":"PMC_28411387","title":"Prophylactic dissection of level V in primary mucosal SCC in the clinically N positive neck: A systematic review.","date":"2017","source":"The Laryngoscope","url":"https://pubmed.ncbi.nlm.nih.gov/28411387","citation_count":12,"is_preprint":false},{"pmid":"39061218","id":"PMC_39061218","title":"SerpinB3: A Multifaceted Player in Health and Disease-Review and Future Perspectives.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/39061218","citation_count":11,"is_preprint":false},{"pmid":"38792976","id":"PMC_38792976","title":"BIA-ALCL and BIA-SCC: Updates on Clinical Features and Genetic Mutations for Latest Recommendations.","date":"2024","source":"Medicina (Kaunas, Lithuania)","url":"https://pubmed.ncbi.nlm.nih.gov/38792976","citation_count":11,"is_preprint":false},{"pmid":"29524519","id":"PMC_29524519","title":"SerpinB3 induces dipeptidyl-peptidase IV/CD26 expression and its metabolic effects in hepatocellular carcinoma.","date":"2018","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29524519","citation_count":11,"is_preprint":false},{"pmid":"33407064","id":"PMC_33407064","title":"SCC: an accurate imputation method for scRNA-seq dropouts based on a mixture model.","date":"2021","source":"BMC bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/33407064","citation_count":11,"is_preprint":false},{"pmid":"20036889","id":"PMC_20036889","title":"Expression of VEGF, VEGF-C and VEGFR-2 in in situ and invasive SCC of cervix.","date":"2010","source":"Frontiers in bioscience (Elite edition)","url":"https://pubmed.ncbi.nlm.nih.gov/20036889","citation_count":11,"is_preprint":false},{"pmid":"40546127","id":"PMC_40546127","title":"MYC/TET3-Regulated TMEM65 Activates OXPHOS-SERPINB3 Pathway to Promote Progression and Cisplatin Resistance in Triple-Negative Breast Cancer.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40546127","citation_count":10,"is_preprint":false},{"pmid":"22026959","id":"PMC_22026959","title":"Tissue specific expression and estrogen regulation of SERPINB3 in the chicken 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pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/36657604","citation_count":9,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50555,"output_tokens":6448,"usd":0.124192,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15475,"output_tokens":5321,"usd":0.1052,"stage2_stop_reason":"end_turn"},"total_usd":0.229392,"stage1_batch_id":"msgbatch_0147LFpL5iCPFZF66xp23BqC","stage2_batch_id":"msgbatch_01Crtwc6eCsZh1CrnfJhY7J7","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"Recombinant SERPINB3 (SCCA1) inhibits chymotrypsin and cathepsin L in vitro, establishing it as an inhibitory-type serpin targeting cysteine and serine proteases.\",\n      \"method\": \"In vitro protease inhibition assay with recombinant protein\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay with recombinant protein, replicated across multiple studies in the corpus\",\n      \"pmids\": [\"9817978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SERPINB3 (SCCA1) suppresses NK cell migration induced by monocyte chemoattractant protein-1 in vitro, and this antichemotactic effect is abrogated by mutation of the reactive site loop, demonstrating that the anti-protease activity is required.\",\n      \"method\": \"NK cell migration assay with recombinant SCCA1 and reactive-site loop mutant\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro functional assay with mutagenesis establishing mechanistic requirement of the reactive site loop; single lab but two orthogonal methods (migration assay + mutagenesis)\",\n      \"pmids\": [\"11280721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Antisense suppression of SCCA (SERPINB3) in SCC tumor cells in vivo leads to increased apoptosis and NK cell infiltration, reducing tumor growth in nude mice.\",\n      \"method\": \"Antisense retroviral knockdown in vivo + immunohistochemistry of tumor tissue\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined cellular phenotypes (apoptosis and NK infiltration); single lab\",\n      \"pmids\": [\"11280721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SERPINB3 expression in HepG2 cells induces epithelial-mesenchymal transition (EMT), evidenced by decreased E-cadherin, increased β-catenin and vimentin, loss of desmosomes, and increased cell migration, invasion, and anchorage-independent growth. These effects occur at both autocrine and paracrine levels and are independent of the anti-protease activity of the protein (active-loop deleted mutant retains scatter activity).\",\n      \"method\": \"Stable transfection of SERPINB3 in HepG2 cells; exogenous recombinant protein addition to HepG2/MDCK cells; active-loop deleted mutant; wound healing/invasion assays; ultrastructural analysis\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transfection, exogenous protein, loss-of-function mutant, invasion assays, ultrastructure); replicated paracrine and autocrine models in single rigorous study\",\n      \"pmids\": [\"20527027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SERPINB3 upregulates TGF-β1 mRNA and protein in transfected hepatocytes (primary human hepatocytes, HepG2, Huh7), and the integrity of the reactive site loop is required for this effect.\",\n      \"method\": \"Transfection of intact SERPINB3 or reactive-site loop deleted mutants; qRT-PCR and immunoassay for TGF-β1; correlation in liver biopsies\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of reactive site loop identifies mechanistic requirement; multiple cell lines tested; single lab\",\n      \"pmids\": [\"20212457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of wild-type SERPINB3 resolved at 2.7 Å, and molecular modelling revealed that the SCCA-PD polymorphic variant (Gly351Ala in reactive center loop) has increased hydrophobic profile, conferring greater cathepsin L and papain inhibitory activity and higher JNK1 inhibitory effect compared to wild-type.\",\n      \"method\": \"X-ray crystallography; in vitro kinetic analysis with recombinant proteins; JNK activity assay; 3D homology modelling\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus in vitro kinetic assay with mutagenesis-equivalent polymorphic variant; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21383048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SERPINB3 is transcriptionally upregulated by oncogenic Ras via the MAPK pathway and the ETS family transcription factor PEA3. Increased SERPINB3 expression leads to inhibition of protein turnover, induction of the unfolded protein response (UPR), and NF-κB activation, which are essential for Ras-mediated cytokine production (e.g., IL-6) and tumor growth.\",\n      \"method\": \"Transcriptional reporter assays; genetic knockdown/overexpression; NF-κB and UPR pathway biochemical assays; mouse tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (reporter assays, KD/OE, pathway assays, in vivo models) in single study; confirmed in human tumor specimens\",\n      \"pmids\": [\"24759783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SERPINB3 (SCCA1) overexpression in mammary epithelial cells promotes oncogenic transformation and EMT, and induces a prolonged non-lethal UPR that activates NF-κB and IL-6 autocrine signaling to drive pro-tumorigenic inflammation.\",\n      \"method\": \"Stable overexpression and siRNA knockdown; UPR and NF-κB reporter assays; IL-6 ELISA; mouse mammary tumor model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain/loss-of-function, multiple pathway readouts, in vivo confirmation; independent replication of UPR/NF-κB mechanism across two labs (PMID 24759783)\",\n      \"pmids\": [\"25213322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SERPINB3 localizes to mitochondrial inner compartments (fraction increases under oxidative stress) and protects hepatoma cells from doxorubicin/cisplatin-induced death by inhibiting mitochondrial respiratory Complex I, thereby reducing ROS generation and preventing mitochondrial permeability transition pore opening.\",\n      \"method\": \"Subcellular fractionation; mitochondrial ROS measurement; PTP opening assays; cell viability assays with pro-oxidant chemotherapeutics; co-immunoprecipitation with Complex I\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct fractionation plus functional assays (ROS, PTP, cell viability) linking mitochondrial localization to mechanism; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24810714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SERPINB3 upregulates Myc through two mechanisms in hepatoma cells and transgenic mice: (1) direct inhibition of calpain protease activity, preventing calpain-mediated cleavage of Myc into its non-oncogenic cytoplasmic form (Myc-nick); (2) indirect activation of the Yap/Hippo pathway, which transcriptionally increases Myc. Recombinant SerpinB3 inhibits calpain activity in vitro.\",\n      \"method\": \"Transgenic mouse overexpression; hepatoma cell transfection; in vitro calpain inhibition assay; Yap pathway analysis; co-IP; Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic assay (calpain inhibition) plus pathway epistasis (Yap/Hippo) and in vivo transgenic model; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26634820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Hypoxia up-regulates SERPINB3 transcription, protein synthesis and extracellular release in liver cancer cells specifically through HIF-2α (not HIF-1α) binding to the SERPINB3 promoter, in a redox-sensitive manner requiring intracellular ROS generation.\",\n      \"method\": \"ChIP assay; siRNA silencing of HIF-1α and HIF-2α; ROS measurement; qRT-PCR and Western blot; hypoxia exposure experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly demonstrates HIF-2α binding to promoter; siRNA epistasis distinguishes HIF-1α vs HIF-2α; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25544768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Exogenous recombinant SerpinB3 added to activated hepatic stellate cells (HSC/MFs and LX2) upregulates pro-fibrogenic gene expression and promotes oriented migration but not proliferation. In transgenic mice overexpressing SerpinB3 in hepatocytes, chronic liver injury leads to increased fibrogenic gene expression, collagen deposition, and αSMA-positive HSC/MFs, confirming paracrine pro-fibrogenic activity.\",\n      \"method\": \"Recombinant protein addition to primary HSC/MF cultures and LX2 cells; transgenic mouse models (CCl4 and MCD diet); qRT-PCR; immunohistochemistry\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro gain-of-function with recombinant protein confirmed in two independent in vivo mouse models; single lab\",\n      \"pmids\": [\"28611447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MiR-122 directly targets the SERPINB3 mRNA 3'UTR as demonstrated by luciferase assay; miR-122 transfection decreased SERPINB3 mRNA and protein, while miR-122 inhibition increased SERPINB3 expression. Overexpression of SERPINB3 blunted the sensitizing effect of miR-122 on sorafenib treatment.\",\n      \"method\": \"Luciferase reporter assay; miR-122 transfection/inhibition; Western blot; cell viability assay\",\n      \"journal\": \"Journal of clinical medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — luciferase assay directly demonstrates miR-122/SERPINB3 mRNA interaction; single lab, multiple validation methods\",\n      \"pmids\": [\"30717317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SERPINB3 inhibits cathepsin L and protects cervical cancer cells from radiation-induced lysoptosis (lysosomal cell death). Genetic knockout of SERPINB3 sensitizes cells to radiation-induced necrotic death; rescue with wild-type SERPINB3 but not a reactive site loop mutant restores protection, demonstrating that protease inhibitory activity is required.\",\n      \"method\": \"CRISPR/genetic knockout; wild-type vs. reactive-site loop mutant rescue; cell death assays (necrosis, apoptosis markers); cathepsin L genetic knockdown; transcriptomics\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis establishes mechanistic requirement of inhibitory activity; KO + rescue design; cathepsin L identified as downstream effector by genetic KD; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35022555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SERPINB3 suppresses antitumor immunity by promoting STAT-dependent expression of chemokines CXCL1/CXCL8 and alarmins S100A8/S100A9, which recruit monocytes and myeloid-derived suppressor cells (MDSCs), thereby inhibiting cytotoxic T cell function. Inhibition of STAT activation by ruxolitinib or siRNA abrogates CXCL1/8 and S100A8/A9 expression in SERPINB3-expressing cells.\",\n      \"method\": \"SERPINB3 overexpression/knockdown; STAT inhibitor (ruxolitinib); STAT siRNA; monocyte/MDSC migration assays; mouse tumor models; flow cytometry of immune infiltrates\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis via STAT inhibition/siRNA places SERPINB3 upstream of STAT; in vivo KD confirms immune phenotype; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"37279067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SerpinB3 is essential for glioblastoma cancer stem cell (CSC) survival and maintenance by buffering cathepsin L-mediated lysosomal cell death; knockdown of SerpinB3 increases cathepsin L-dependent apoptosis and radiosensitivity in CSCs.\",\n      \"method\": \"Genetic depletion (shRNA/siRNA); cathepsin L activity/apoptosis assays; CSC sphere formation; mouse xenograft models; radiation sensitivity assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (cathepsin L-mediated death); in vivo xenograft confirmation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36103817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SERPINB3 inhibits the cysteine protease calpain, a key enzyme in the MYC degradation pathway, thereby stabilizing MYC and driving metabolic reprogramming (heightened carnitine/acylcarnitine and amino acid metabolism) and the basal-like/squamous subtype in pancreatic cancer. SERPINB3 transgene expression enhances invasion in vitro and promotes lung metastasis in a xenograft model.\",\n      \"method\": \"SERPINB3 transgene expression; in vitro invasion assays; mouse xenograft model; calpain activity assays; metabolome analyses\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — calpain inhibition assay mechanistically links SERPINB3 to MYC stabilization; in vivo confirmation; metabolomics provides orthogonal evidence; replicates and extends findings from PMID 26634820\",\n      \"pmids\": [\"37980563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SERPINB3 downregulation (by HPV-E6/E7) reduces USP1-mediated deubiquitination of FANCD2-FANCI in the Fanconi anemia DNA repair pathway, thereby impairing cisplatin-induced DNA interstrand crosslink repair and increasing HNSCC cell apoptosis.\",\n      \"method\": \"SERPINB3 siRNA knockdown; FANCD2-FANCI ubiquitination assays; DNA damage repair assays; patient-derived xenograft model with nanoparticle siRNA delivery\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical pathway assay (ubiquitination of FANCD2-FANCI) links SERPINB3 KD to FA pathway; in vivo PDX confirmation; single lab\",\n      \"pmids\": [\"36382555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SERPINB3 is expressed on the surface of CD27+ B lymphocytes in healthy individuals; this surface expression is reduced in HCV-infected patients and absent in SLE patients.\",\n      \"method\": \"Flow cytometry; confocal microscopy; correlation with CD27 expression\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization by flow cytometry and confocal; single lab, no functional consequence established\",\n      \"pmids\": [\"22829702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SERPINB3 is expressed in hepatic progenitor cells (EpCAM+ sorted cells from fetal and adult livers, CK-7/CK-19/EpCAM/CD-90 positive cells in cirrhotic livers); in a mouse model of liver injury, SerpinB3 expression progressively increases while activated caspase-3 decreases, consistent with an anti-apoptotic role in progenitor cells.\",\n      \"method\": \"Cell sorting; immunohistochemistry; RT-PCR with sequencing; mouse injury model (LPS/D-galactosamine)\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by cell sorting and IHC with functional correlate (inverse caspase-3); multiple methods; single lab\",\n      \"pmids\": [\"24517394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SERPINB3 attenuates cytochrome c release from mitochondria, contributing to apoptosis resistance. This was documented in vitro and in vivo across multiple studies.\",\n      \"method\": \"Cytochrome c release assay; transfection; in vitro apoptosis induction\",\n      \"journal\": \"Autoimmunity reviews / Annals of hepatology (review citing in vitro and in vivo experiments)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — documented in multiple studies; mechanism further specified in PMID 24810714 (Complex I inhibition preventing ROS/PTP); multiple labs\",\n      \"pmids\": [\"19332150\", \"25332258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In atopic dermatitis, SERPINB3/B4 (mouse homolog Serpinb3a) promotes barrier dysfunction and early inflammatory responses. Serpinb3a-null mice show attenuated transepidermal water loss, reduced epidermal thickness, and reduced skin inflammation after allergen exposure. Silencing of SERPINB3/B4 in human keratinocytes decreased S100A8 expression, placing SERPINB3/B4 upstream of the S100A8-mediated inflammatory response.\",\n      \"method\": \"Serpinb3a knockout mouse; topical allergen challenge; TEWL measurement; RNA-seq; siRNA silencing in human keratinocytes\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined phenotype confirmed by human keratinocyte siRNA; RNA-seq identifies pathway; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25111616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TEAD4 transcriptionally regulates SERPINB3/B4 expression in psoriatic keratinocytes, and SERPINB3/B4 mediates TEAD4-dependent chemokine secretion that promotes T cell migration.\",\n      \"method\": \"TEAD4 siRNA knockdown; SERPINB3/B4 siRNA; chemokine ELISA; T cell migration assay\",\n      \"journal\": \"Immunobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA epistasis places SERPINB3 downstream of TEAD4 and upstream of chemokine secretion; single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"32962824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RCL-mutagenesis of SERPINB3 scaffold can redirect its inhibitory specificity: replacing the native RCL with sequences targeting furin or TMPRSS2 generates variants that inhibit these proteases (not cathepsin L), block SARS-CoV-2 spike protein cleavage in vitro, and suppress SARS-CoV-2 replication in cells. The TMPRSS2-targeting variant (B3-TMP) shows 18-fold improvement in inhibition rate constant over alpha-1 antitrypsin.\",\n      \"method\": \"Reactive center loop mutagenesis; in vitro protease inhibition kinetic assays; pseudoparticle entry assay; live virus replication assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and kinetic measurements; functional cell-based validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36293378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SERPINB3 induces a positive feedback loop between COX-2 and β-catenin in colorectal cancer cells; cell lines with high SerpinB3 expression show higher COX-2 and β-catenin levels, greater proliferation, and invasion compared to controls.\",\n      \"method\": \"Cell line comparison with differential SERPINB3 expression; Western blot for COX-2 and β-catenin; proliferation and invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — correlation-based in vitro evidence in cell lines; no direct KD/rescue experiment described; single lab\",\n      \"pmids\": [\"28178650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SERPINB3 expression is transcriptionally activated by HIF1α downstream of ROS produced by TMEM65-enhanced OXPHOS in triple-negative breast cancer; SERPINB3 in turn promotes TNBC stemness, progression, and cisplatin resistance.\",\n      \"method\": \"TMEM65 knockdown/overexpression; ROS measurement; HIF1α inhibition; SERPINB3 expression analysis; cisplatin sensitivity assays; in vivo tumor models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — pathway epistasis placing SERPINB3 downstream of TMEM65/ROS/HIF1α; single lab; SERPINB3 not directly manipulated as primary subject\",\n      \"pmids\": [\"40546127\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SERPINB3 is a cross-class serine/cysteine protease inhibitor that acts through its reactive center loop to inhibit cathepsin L, calpain, and other proteases, thereby blocking apoptosis (preventing cytochrome c release and lysoptosis), stabilizing MYC (by preventing calpain-mediated cleavage), activating NF-κB and IL-6 via the unfolded protein response, inhibiting NK cell chemotaxis, localizing to mitochondria to suppress Complex I-mediated ROS and permeability transition pore opening, transcriptionally responding to oncogenic Ras (via MAPK/PEA3) and hypoxia (via HIF-2α/ROS), and promoting EMT, pro-fibrogenic signaling, and immune evasion through STAT-dependent chemokine production.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SERPINB3 is an inhibitory-type serpin that uses its reactive center loop (RCL) to inhibit cysteine and serine proteases — including cathepsin L, calpain, and chymotrypsin — and thereby acts as a broad cytoprotective and pro-tumorigenic effector across epithelial cancers and tissue injury [#0, #5]. Many of its downstream activities are RCL-dependent: protease inhibition is required for its suppression of NK cell chemotaxis [#1] and for protection against radiation-induced cathepsin L-mediated lysosomal cell death (lysoptosis), where genetic knockout sensitizes cells to necrotic death and only wild-type, not RCL-mutant, protein restores protection [#13]. This cathepsin L-buffering function sustains survival of glioblastoma cancer stem cells [#15]. By inhibiting calpain, SERPINB3 prevents cleavage of MYC into its non-oncogenic form and additionally raises MYC via Yap/Hippo activation, stabilizing MYC to drive metabolic reprogramming and aggressive squamous/basal tumor phenotypes [#9, #16]. SERPINB3 also drives epithelial-mesenchymal transition and pro-fibrogenic signaling through autocrine and paracrine routes — including TGF-\\u03b21 induction and activation of hepatic stellate cells — with EMT being independent of anti-protease activity but TGF-\\u03b21 induction requiring an intact RCL [#3, #4, #11]. It promotes tumor-permissive inflammation and immune evasion by inducing a prolonged non-lethal unfolded protein response that activates NF-\\u03baB and IL-6 [#6, #7], and by driving STAT-dependent CXCL1/CXCL8 and S100A8/S100A9 production that recruits myeloid-derived suppressor cells and suppresses cytotoxic T cells [#14]. SERPINB3 localizes to mitochondria where it inhibits respiratory Complex I to limit ROS and block permeability transition pore opening, contributing to apoptosis resistance and chemoresistance [#8]. Its expression is induced by oncogenic Ras via MAPK/PEA3 [#6] and by hypoxia through HIF-2\\u03b1 in a redox-dependent manner [#10], and is repressed post-transcriptionally by miR-122 [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the biochemical identity of SERPINB3 as a functional protease inhibitor rather than a non-inhibitory serpin, defining its core molecular activity.\",\n      \"evidence\": \"In vitro protease inhibition assays with recombinant protein against chymotrypsin and cathepsin L\",\n      \"pmids\": [\"9817978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full physiological substrate spectrum not defined in this assay\", \"No cellular or in vivo context for the inhibition\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked SERPINB3 protease activity to immune evasion by showing it suppresses NK cell chemotaxis in an RCL-dependent manner, and that knockdown restores apoptosis and NK infiltration in tumors.\",\n      \"evidence\": \"NK cell migration assay with RCL mutant; antisense knockdown in nude mouse SCC tumors with IHC\",\n      \"pmids\": [\"11280721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease target mediating antichemotactic effect not identified\", \"Mechanism connecting protease inhibition to migration suppression unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed SERPINB3 drives EMT and pro-fibrogenic TGF-\\u03b21 signaling, separating an anti-protease-independent EMT/scatter activity from an RCL-dependent TGF-\\u03b21 induction.\",\n      \"evidence\": \"Transfection, exogenous recombinant protein, active-loop-deleted mutants, invasion/ultrastructure assays in HepG2/Huh7/hepatocytes\",\n      \"pmids\": [\"20527027\", \"20212457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor or signaling intermediary for paracrine scatter activity unknown\", \"How an RCL-independent activity operates mechanistically is unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided structural basis for SERPINB3 inhibition and showed an RCL polymorphism (Gly351Ala) tunes cathepsin L/papain and JNK1 inhibitory potency.\",\n      \"evidence\": \"X-ray crystallography at 2.7 \\u00c5, in vitro kinetics with recombinant variants, JNK activity assay, homology modelling\",\n      \"pmids\": [\"21383048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the polymorphism in vivo not established\", \"Mechanism of JNK inhibition not biochemically defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined SERPINB3 as an oncogenic effector downstream of Ras/MAPK/PEA3 that sustains tumor inflammation by inducing a non-lethal UPR-driven NF-\\u03baB/IL-6 program, replicated in two independent epithelial systems.\",\n      \"evidence\": \"Reporter assays, reciprocal KD/OE, UPR/NF-\\u03baB pathway readouts, IL-6 ELISA, mouse tumor models\",\n      \"pmids\": [\"24759783\", \"25213322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How protease inhibition triggers the UPR is unclear\", \"Molecular link between SERPINB3 and proteostasis disruption undefined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a mitochondrial localization and function for SERPINB3, where it inhibits Complex I to limit ROS and block PTP opening, providing a mechanism for chemoresistance and reduced cytochrome c release.\",\n      \"evidence\": \"Subcellular fractionation, mitochondrial ROS and PTP assays, co-IP with Complex I, viability assays with pro-oxidant drugs\",\n      \"pmids\": [\"24810714\", \"19332150\", \"25332258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a serpin reaches the mitochondrial inner compartment is unknown\", \"Direct Complex I subunit target not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established calpain inhibition as a route by which SERPINB3 stabilizes MYC, complemented by Yap/Hippo-mediated transcriptional MYC upregulation.\",\n      \"evidence\": \"In vitro calpain inhibition assay, hepatoma transfection, transgenic mice, Yap pathway analysis, co-IP\",\n      \"pmids\": [\"26634820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking SERPINB3 to Yap activation not resolved\", \"Relative contribution of the two MYC mechanisms unquantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Placed SERPINB3 in hypoxic signaling, showing HIF-2\\u03b1 (not HIF-1\\u03b1) drives its transcription and extracellular release in a ROS-dependent manner.\",\n      \"evidence\": \"ChIP, HIF-1\\u03b1/HIF-2\\u03b1 siRNA, ROS measurement, qRT-PCR/Western under hypoxia\",\n      \"pmids\": [\"25544768\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Source of the redox signal selecting HIF-2\\u03b1 not defined\", \"Function of secreted SERPINB3 in the hypoxic niche unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed paracrine pro-fibrogenic activity, showing recombinant SERPINB3 activates hepatic stellate cells and hepatocyte-overexpressing mice develop more fibrosis under chronic injury.\",\n      \"evidence\": \"Recombinant protein on HSC/MF and LX2 cells; CCl4 and MCD-diet transgenic mouse models; qRT-PCR/IHC\",\n      \"pmids\": [\"28611447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stellate-cell receptor for SERPINB3 not identified\", \"Signaling pathway driving migration vs. proliferation split unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified post-transcriptional control of SERPINB3 by miR-122 and linked its expression to sorafenib resistance.\",\n      \"evidence\": \"Luciferase 3'UTR reporter, miR-122 transfection/inhibition, Western blot, viability assay\",\n      \"pmids\": [\"30717317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contexts where miR-122 regulates SERPINB3 not mapped\", \"Mechanism of SERPINB3-driven drug resistance not specified here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that RCL-dependent cathepsin L inhibition protects against radiation-induced lysoptosis and sustains cancer stem cell survival, cementing the protease-inhibition-to-cell-death-protection axis.\",\n      \"evidence\": \"CRISPR KO with WT vs. RCL-mutant rescue, cathepsin L genetic KD, cell death assays, transcriptomics; CSC shRNA depletion with xenografts and radiosensitivity assays\",\n      \"pmids\": [\"35022555\", \"36103817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger releasing cathepsin L to the cytosol not defined\", \"Generality across non-irradiated lysosomal death stimuli unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established SERPINB3 as a driver of immune evasion via STAT-dependent chemokine and alarmin production that recruits MDSCs and suppresses cytotoxic T cells.\",\n      \"evidence\": \"OE/KD, ruxolitinib and STAT siRNA, monocyte/MDSC migration, mouse tumor models, immune-infiltrate flow cytometry\",\n      \"pmids\": [\"37279067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SERPINB3 activates STAT signaling is not defined\", \"Direct vs. indirect role of protease inhibition in this axis unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed the SERPINB3 scaffold is RCL-programmable, generating engineered variants that inhibit furin/TMPRSS2 and block SARS-CoV-2 entry, confirming RCL identity dictates target specificity.\",\n      \"evidence\": \"RCL mutagenesis, kinetic inhibition assays, pseudoparticle entry and live-virus replication assays\",\n      \"pmids\": [\"36293378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native SERPINB3 does not target these proteases\", \"In vivo antiviral utility not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected SERPINB3 to DNA crosslink repair, showing its HPV-driven downregulation impairs USP1-dependent FANCD2-FANCI deubiquitination and sensitizes HNSCC to cisplatin.\",\n      \"evidence\": \"siRNA KD, FANCD2-FANCI ubiquitination assays, DNA repair assays, PDX with nanoparticle siRNA\",\n      \"pmids\": [\"36382555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between a protease inhibitor and USP1 activity unexplained\", \"Single-lab finding without reciprocal validation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended SERPINB3 biology beyond cancer, showing the mouse homolog promotes epidermal barrier dysfunction and S100A8-driven inflammation in atopic dermatitis.\",\n      \"evidence\": \"Serpinb3a-null mice with allergen challenge, TEWL, RNA-seq; human keratinocyte siRNA\",\n      \"pmids\": [\"25111616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease target in skin inflammation not identified\", \"Relationship between human SERPINB3 and mouse Serpinb3a function not fully reconciled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed SERPINB3 downstream of a TMEM65-OXPHOS-ROS-HIF1\\u03b1 axis in triple-negative breast cancer, driving stemness and cisplatin resistance.\",\n      \"evidence\": \"TMEM65 KD/OE, ROS measurement, HIF1\\u03b1 inhibition, SERPINB3 expression analysis, cisplatin assays, in vivo models\",\n      \"pmids\": [\"40546127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SERPINB3 not directly manipulated as primary subject\", \"Apparent HIF1\\u03b1 dependence contrasts with HIF-2\\u03b1 selectivity reported in liver cancer\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SERPINB3 transduces protease inhibition into the broad set of downstream programs (UPR/NF-\\u03baB, STAT signaling, Yap activation, mitochondrial Complex I inhibition) at the molecular level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying mechanism connecting cytosolic protease inhibition to nuclear/mitochondrial signaling outputs\", \"Receptors mediating paracrine/extracellular SERPINB3 activity unidentified\", \"How SERPINB3 localizes across cytosol, mitochondria, and cell surface is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 9, 13, 16, 23]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 9, 13, 16, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [10, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7, 14, 16]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 15, 20]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 14, 21]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 7, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CTSL\",\n      \"CAPN\",\n      \"MYC\",\n      \"NDUFS (Complex I)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win"}}