{"gene":"SERPINA3","run_date":"2026-04-28T20:42:07","timeline":{"discoveries":[{"year":2007,"finding":"SERPINA3 (alpha-1-antichymotrypsin/ACT) functions as a serine protease inhibitor; its structure, regulatory elements, tissue-specific expression, and physiological roles including acute-phase response were characterized. It inhibits cathepsin G and other serine proteases.","method":"Review synthesizing proteomic, transcriptomic, and genomic studies","journal":"Frontiers in bioscience","confidence":"Medium","confidence_rationale":"Tier 3 — comprehensive review consolidating prior experimental work; no single new experiment described","pmids":["17485262"],"is_preprint":false},{"year":2005,"finding":"SERPINA3 (serpina3) is expressed by multiple hematopoietic cell populations in bone marrow and is down-regulated at both mRNA and protein levels during G-CSF- or chemotherapy-induced hematopoietic progenitor mobilization, shifting the balance between serine protease inhibitors and neutrophil serine proteases to allow progenitor release.","method":"Protein and mRNA expression analysis (ELISA, RT-PCR) in bone marrow during mobilization; tissue comparison (bone marrow vs. liver)","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 — orthogonal methods (protein and mRNA), functional context established via tissue-specific expression changes","pmids":["15795238"],"is_preprint":false},{"year":2008,"finding":"Orphan nuclear receptor Nur77 directly binds to the NBRE element (-182 to -175) in the SERPINA3 promoter, transactivating SERPINA3 gene expression, as demonstrated by EMSA, ChIP, luciferase reporter assays, Nur77 overexpression, and RNA interference-mediated knockdown.","method":"Luciferase reporter assay, EMSA, chromatin immunoprecipitation (ChIP), Nur77 overexpression, RNA interference knockdown","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (reporter assay, EMSA, ChIP, gain/loss of function) in single study","pmids":["18248459"],"is_preprint":false},{"year":2017,"finding":"ApoA4 stimulates SERPINA3 gene expression in mouse hepatocytes in a dose- and time-dependent manner; the transcriptional response is mediated by ApoA4 binding to nuclear receptors NR4A1 and NR1D1 on the SERPINA3 promoter, as confirmed by ChIP, luciferase assay, and RNA interference of NR4A1 or NR1D1.","method":"ChIP, luciferase reporter assay, RNA interference, RT-PCR, in vivo and in vitro hepatocyte stimulation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (ChIP, reporter assay, RNAi) in single study confirming promoter binding and transcriptional regulation","pmids":["28412351"],"is_preprint":false},{"year":2019,"finding":"STAT3 directly regulates SERPINA3 transcription in human melanoma cells; STAT3 knockdown reduces SERPINA3 expression, and STAT3 physically associates with defined STAT3-binding sites in the SERPINA3 promoter as validated by ChIP-qPCR. SERPINA3 is functionally involved in STAT3-mediated regulation of melanoma migration and invasion.","method":"Gene expression profiling, STAT3 siRNA knockdown, chromatin immunoprecipitation (ChIP)-qPCR, migration and invasion assays","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal epistasis (STAT3 KD reduces SERPINA3), direct promoter binding by ChIP, functional readout (migration/invasion)","pmids":["31278347"],"is_preprint":false},{"year":2014,"finding":"SERPINA3 promotes endometrial cancer cell proliferation by regulating G2/M cell cycle checkpoint and inhibiting apoptosis; this pro-proliferative effect is mediated through activation of MAPK/ERK1/2 and PI3K/AKT signaling pathways.","method":"SERPINA3 overexpression/knockdown, cell cycle analysis, apoptosis assay, western blot for ERK1/2 and AKT phosphorylation","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 2–3 — gain/loss of function with pathway analysis by western blot; single lab","pmids":["24817931"],"is_preprint":false},{"year":2018,"finding":"SERPINA3 silencing inhibits the migration, invasion, and liver metastasis of colon cancer cells, and reduces MMP-2 and MMP-9 expression levels both in vitro (ELISA) and in vivo (immunohistochemistry in mouse liver metastasis model).","method":"siRNA knockdown, wound-healing assay, Transwell invasion assay, ELISA (MMP-2/9), mouse xenograft liver metastasis model, immunohistochemistry","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo loss-of-function with mechanistic link to MMP-2/9","pmids":["29855767"],"is_preprint":false},{"year":2017,"finding":"SERPINA3 knockdown significantly decreases migration and matrix invasion of melanoma cells without affecting proliferation, establishing a pro-migration and pro-invasion function for SERPINA3 in melanoma.","method":"siRNA knockdown, cell migration assay, matrix invasion assay, cell proliferation assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2–3 — specific loss-of-function with defined cellular phenotype readouts","pmids":["27213583"],"is_preprint":false},{"year":2021,"finding":"SERPINA3 overexpression in triple-negative breast cancer cells promotes cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) by upregulating EMT markers and EZH2; SERPINA3 overexpression also reduces sensitivity to cisplatin.","method":"Overexpression and knockdown, wound healing, Transwell assay, CCK-8 proliferation assay, western blot for EMT markers and EZH2, drug sensitivity assay","journal":"Breast cancer (Tokyo, Japan)","confidence":"Medium","confidence_rationale":"Tier 2–3 — gain and loss of function with EMT marker analysis; single lab","pmids":["33569740"],"is_preprint":false},{"year":2021,"finding":"SERPINA3 regulates vascular smooth muscle cell (VSMC) proliferation and migration through the NF-κB signaling pathway; SERPINA3 knockdown in rat aortic smooth muscle cells attenuated proliferation, migration, and inhibited phosphorylated IκBα and its downstream pathway. Secreted SERPINA3 protein increases inflammatory factor expression in human umbilical vein endothelial cells (HUVECs).","method":"siRNA knockdown in RASMCs, EdU proliferation assay, scratch migration assay, western blot and RT-PCR for NF-κB pathway components, SERPINA3 protein stimulation of HUVECs","journal":"Frontiers in cardiovascular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — loss-of-function with pathway analysis; in vitro only; single lab","pmids":["34957248"],"is_preprint":false},{"year":2021,"finding":"CircSERPINA3 stabilizes SERPINA3 mRNA by recruiting the RNA-binding protein BUD13, and also acts as a miR-653-5p sponge to competitively release SERPINA3 from miR-653-5p-mediated suppression. SERPINA3 itself inhibits apoptosis and promotes aerobic glycolysis and autophagy in prostate cancer cells.","method":"RT-qPCR, RNA pulldown, luciferase reporter assay (miRNA sponge), RIP (RNA immunoprecipitation), functional assays (apoptosis, autophagy, glycolysis)","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 — multiple mechanism assays (RIP, reporter, functional) in single lab","pmids":["34861864"],"is_preprint":false},{"year":2023,"finding":"SERPINA3 overexpression in lung cancer cells upregulates SPOP and inhibits NF-κB p65, suppressing tumor cell growth, proliferation, migration, and invasion; mechanistically identified by data-independent acquisition mass spectrometry (DIA-MS) and validated by western blot in cell lines and mouse xenograft tumors.","method":"SERPINA3 overexpression, DIA-MS proteomics, western blot, xenograft mouse model, proliferation and invasion assays","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 — proteomic discovery + in vitro and in vivo validation of SPOP/NF-κB mechanism","pmids":["37417362"],"is_preprint":false},{"year":2022,"finding":"Human SERPINA3 overexpression in mice induces neocortical folding and increases outer radial glia (oRG) proliferation and upper-layer neuron numbers; SERPINA3 promotes oRG proliferation by binding to the Glo1 promoter, with Glo1 identified as a downstream target involved in SERPINA3-induced gyrification.","method":"SERPINA3 overexpression in mouse brain, ChIP (SERPINA3 binding to Glo1 promoter), histological analysis, behavioral cognitive testing","journal":"Cell discovery","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct promoter binding; in vivo gain-of-function with defined cellular and behavioral phenotypes","pmids":["36414636"],"is_preprint":false},{"year":2022,"finding":"SERPINA3 inhibits NF-κB activation and downstream inflammatory mediators (COX2, iNOS, TNF-α, IL-6, MMP13, MMP9) in osteoarthritis chondrocytes; sinensetin exerts its chondroprotective effects partly by regulating SERPINA3 expression.","method":"In vitro IL-1β-stimulated OA chondrocytes, siRNA/pharmacological modulation of SERPINA3, western blot for NF-κB and inflammatory markers, rat OA in vivo model","journal":"Food & function","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic link between SERPINA3 and NF-κB in vitro and in vivo; single lab","pmids":["36056701"],"is_preprint":false},{"year":2017,"finding":"SERPINA3 is strongly up-regulated at both mRNA and protein levels in the brain of all human prion disease subtypes, suggesting involvement in prion disease pathogenesis and progression; this is distinct from the mild up-regulation observed in Alzheimer's disease.","method":"RT-qPCR on frontal cortex samples (128 prion disease patients, 14 AD patients, 30 controls), protein-level confirmation","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 — expression analysis without direct mechanistic experiment; included as it provides molecular context for pathogenic role","pmids":["29142239"],"is_preprint":false},{"year":2022,"finding":"SERPINA3 is upregulated in renal tubules of diabetic nephropathy patients; as an inhibitor of mast cell chymase, SERPINA3 is proposed to protect against renal tubular injury by inhibiting mast cell proliferation/activation and chymase activity.","method":"RNA-seq dataset analysis, immunohistochemistry of human renal tubular biopsies for SERPINA3 and chymase expression, mast cell infiltration analysis","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 — expression-based with prior biochemical knowledge of serine protease inhibitory function; no direct functional experiment on chymase inhibition reported here","pmids":["36304455"],"is_preprint":false}],"current_model":"SERPINA3 (alpha-1-antichymotrypsin) is a serine protease inhibitor (targeting cathepsin G, chymase, and related proteases) secreted as an acute-phase protein primarily by the liver; its transcription is directly regulated by nuclear receptors Nur77, NR4A1/NR1D1 (via ApoA4), and STAT3; in cancer cells it modulates migration, invasion, and EMT partly through MMP-2/9 regulation, MAPK/ERK and PI3K/AKT signaling, SPOP/NF-κB pathways, and EZH2 upregulation; in the CNS it promotes outer radial glia proliferation and cortical folding via binding to the Glo1 promoter; and in the bone marrow it regulates the protease–antiprotease balance governing hematopoietic progenitor mobilization."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing that SERPINA3 is not merely a hepatic acute-phase protein but is expressed by bone marrow hematopoietic cells and dynamically down-regulated during progenitor mobilization, linking protease–antiprotease balance to stem cell release.","evidence":"ELISA and RT-PCR of bone marrow during G-CSF- or chemotherapy-induced mobilization in human subjects","pmids":["15795238"],"confidence":"Medium","gaps":["No direct demonstration that SERPINA3 loss is required or sufficient for progenitor egress","Identity of the specific serine protease(s) counterbalanced by SERPINA3 in this context not established","Mechanism of SERPINA3 down-regulation during mobilization unknown"]},{"year":2008,"claim":"Identifying the first direct transcriptional regulator of SERPINA3: the orphan nuclear receptor Nur77 binds an NBRE element at −182 to −175 in the SERPINA3 promoter, explaining how nuclear receptor signaling controls acute-phase SERPINA3 expression.","evidence":"EMSA, ChIP, luciferase reporter, Nur77 overexpression and RNAi in human cell lines","pmids":["18248459"],"confidence":"High","gaps":["Physiological stimuli upstream of Nur77 that regulate SERPINA3 in vivo not defined","Contribution of Nur77 versus other transcription factors to hepatic SERPINA3 expression not quantified"]},{"year":2014,"claim":"Demonstrating that SERPINA3 has a cell-autonomous pro-proliferative role in cancer, promoting G2/M progression and inhibiting apoptosis via MAPK/ERK1/2 and PI3K/AKT signaling — shifting understanding from a secreted protease inhibitor to an intracellular signaling modulator.","evidence":"SERPINA3 overexpression/knockdown in endometrial cancer cells with cell cycle, apoptosis, and phospho-western blot readouts","pmids":["24817931"],"confidence":"Medium","gaps":["Direct binding partners mediating MAPK/ERK and PI3K/AKT activation not identified","Whether the protease inhibitory activity is required for the proliferative phenotype is unknown","Findings limited to a single cancer type at this point"]},{"year":2017,"claim":"Extending SERPINA3's oncogenic role to melanoma (pro-migration/invasion without affecting proliferation) and showing that ApoA4-NR4A1/NR1D1 signaling constitutes a second nuclear-receptor-dependent transcriptional axis for SERPINA3 in hepatocytes, broadening understanding of its regulation.","evidence":"siRNA knockdown with migration/invasion assays in melanoma (PMID:27213583); ChIP, luciferase, and RNAi for NR4A1/NR1D1 in mouse hepatocytes (PMID:28412351)","pmids":["27213583","28412351"],"confidence":"Medium","gaps":["The cell-type-specific effects (proliferation vs. migration) are unexplained mechanistically","Whether NR4A1/NR1D1-mediated regulation occurs in extrahepatic tissues is untested"]},{"year":2018,"claim":"Providing in vivo evidence that SERPINA3 promotes cancer metastasis: silencing SERPINA3 reduces colon cancer liver metastasis in a mouse xenograft model, mechanistically linked to decreased MMP-2/9 expression.","evidence":"siRNA knockdown, Transwell invasion assay, ELISA for MMP-2/9, mouse liver metastasis model with IHC","pmids":["29855767"],"confidence":"Medium","gaps":["Whether MMP-2/9 regulation by SERPINA3 is direct or indirect remains unresolved","Role of SERPINA3's protease inhibitory function versus a non-canonical activity in metastasis is unclear"]},{"year":2019,"claim":"Identifying STAT3 as a third direct transcriptional regulator of SERPINA3, binding defined sites in the SERPINA3 promoter in melanoma cells and coupling SERPINA3 expression to STAT3-driven migration and invasion.","evidence":"STAT3 siRNA knockdown, ChIP-qPCR for STAT3 at SERPINA3 promoter, migration and invasion assays in melanoma cells","pmids":["31278347"],"confidence":"High","gaps":["Whether STAT3 regulation of SERPINA3 generalizes beyond melanoma is unknown","Epistatic relationship between Nur77 and STAT3 at the SERPINA3 promoter not addressed"]},{"year":2021,"claim":"Broadening SERPINA3's downstream signaling repertoire: in breast cancer SERPINA3 drives EMT through EZH2 upregulation and reduces cisplatin sensitivity; in vascular smooth muscle cells it promotes proliferation and migration via NF-κB/IκBα phosphorylation; and circSERPINA3 stabilizes SERPINA3 mRNA through BUD13 recruitment and miR-653-5p sponging.","evidence":"Overexpression/knockdown with EMT marker and EZH2 western blot in TNBC (PMID:33569740); siRNA in RASMCs with NF-κB western blot (PMID:34957248); RIP, RNA pulldown, luciferase reporter for circSERPINA3/BUD13/miR-653-5p axis in prostate cancer (PMID:34861864)","pmids":["33569740","34957248","34861864"],"confidence":"Medium","gaps":["Whether EZH2 is a direct or indirect target of SERPINA3 is unknown","The NF-κB effects of SERPINA3 differ in direction across cancer vs. vascular contexts — mechanistic basis unresolved","All findings from single labs without independent replication"]},{"year":2022,"claim":"Revealing a neurodevelopmental role: human SERPINA3 overexpression in mouse brain induces cortical folding by promoting outer radial glia proliferation, with SERPINA3 directly binding the Glo1 promoter as a transcriptional mechanism — an unexpected non-canonical function for a serpin.","evidence":"In vivo SERPINA3 overexpression in mouse brain, ChIP for SERPINA3 at Glo1 promoter, histological and behavioral analysis","pmids":["36414636"],"confidence":"Medium","gaps":["How a secreted protease inhibitor enters the nucleus and acts as a transcriptional regulator is mechanistically unexplained","Whether endogenous SERPINA3 is required for human cortical gyrification is untested","Glo1 downstream effectors mediating oRG proliferation not identified"]},{"year":2022,"claim":"Demonstrating that SERPINA3 modulates NF-κB-dependent inflammation in osteoarthritis chondrocytes, suppressing COX2, iNOS, TNF-α, IL-6, and MMPs — consistent with its anti-inflammatory function via protease inhibition in non-cancer contexts.","evidence":"siRNA and pharmacological modulation in IL-1β-stimulated chondrocytes with NF-κB western blot; rat OA model","pmids":["36056701"],"confidence":"Medium","gaps":["Whether chondroprotective effects require serine protease inhibitory activity specifically is not tested","Findings from a single lab; effect size of SERPINA3 relative to other serpins in OA unknown"]},{"year":2023,"claim":"In lung cancer, SERPINA3 overexpression upregulates SPOP and suppresses NF-κB p65, inhibiting tumor growth — revealing context-dependent tumor-suppressive activity contrasting with its oncogenic role in other cancers.","evidence":"DIA-MS proteomics, western blot validation, xenograft mouse model with SERPINA3 overexpression in lung cancer cells","pmids":["37417362"],"confidence":"Medium","gaps":["Why SERPINA3 is tumor-suppressive in lung cancer but oncogenic in other cancers is mechanistically unexplained","Whether SERPINA3 directly regulates SPOP expression or acts indirectly is not established","Single study; independent replication lacking"]},{"year":null,"claim":"Major open questions remain: (1) how a secreted serpin accesses the nucleus to regulate promoters (Glo1), (2) what determines the context-dependent pro- vs. anti-tumorigenic activity across cancer types, and (3) whether the protease-inhibitory and signaling functions are mechanistically separable.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No nuclear import mechanism or nuclear localization signal identified for SERPINA3","Structure–function dissection separating protease inhibition from intracellular signaling not performed","No crystal structure of SERPINA3 bound to a non-protease partner"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,6,13,15]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,9]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,11]}],"complexes":[],"partners":["NR4A1","NR1D1","STAT3","SPOP","EZH2","BUD13","GLO1"],"other_free_text":[]},"mechanistic_narrative":"SERPINA3 (alpha-1-antichymotrypsin) is a secreted serine protease inhibitor that functions as an acute-phase protein, inhibiting cathepsin G and related proteases, and participates in diverse processes including hematopoietic progenitor mobilization, inflammation, cortical development, and cancer progression [PMID:17485262, PMID:15795238]. Its transcription is directly regulated by the orphan nuclear receptor Nur77 via an NBRE element in the promoter, by NR4A1/NR1D1 in response to ApoA4 signaling in hepatocytes, and by STAT3 in melanoma cells [PMID:18248459, PMID:28412351, PMID:31278347]. In multiple cancer types, SERPINA3 promotes cell proliferation, migration, invasion, and epithelial-mesenchymal transition through MAPK/ERK, PI3K/AKT, NF-κB, and EZH2-dependent mechanisms, and facilitates metastasis partly by upregulating MMP-2/9 [PMID:24817931, PMID:29855767, PMID:33569740, PMID:37417362]. In the developing brain, SERPINA3 overexpression drives outer radial glia proliferation and neocortical gyrification by binding the Glo1 promoter [PMID:36414636]."},"prefetch_data":{"uniprot":{"accession":"P01011","full_name":"Alpha-1-antichymotrypsin","aliases":["Cell growth-inhibiting gene 24/25 protein","Serpin A3"],"length_aa":423,"mass_kda":47.7,"function":"Although its physiological function is unclear, it can inhibit neutrophil cathepsin G and mast cell chymase, both of which can convert angiotensin-1 to the active angiotensin-2","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P01011/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SERPINA3","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SERPINA3","total_profiled":1310},"omim":[{"mim_id":"613490","title":"ALPHA-1-ANTITRYPSIN DEFICIENCY; A1ATD","url":"https://www.omim.org/entry/613490"},{"mim_id":"606963","title":"PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; COPD","url":"https://www.omim.org/entry/606963"},{"mim_id":"118938","title":"CHYMASE 1; CMA1","url":"https://www.omim.org/entry/118938"},{"mim_id":"116830","title":"CATHEPSIN G; CTSG","url":"https://www.omim.org/entry/116830"},{"mim_id":"107400","title":"SERPIN PEPTIDASE INHIBITOR, CLADE A, MEMBER 1; SERPINA1","url":"https://www.omim.org/entry/107400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":8462.6},{"tissue":"pancreas","ntpm":4871.0}],"url":"https://www.proteinatlas.org/search/SERPINA3"},"hgnc":{"alias_symbol":["ACT"],"prev_symbol":["AACT"]},"alphafold":{"accession":"P01011","domains":[{"cath_id":"3.30.497.10","chopping":"43-214_317-363","consensus_level":"medium","plddt":92.5035,"start":43,"end":363},{"cath_id":"2.30.39.10","chopping":"222-314_371-416","consensus_level":"medium","plddt":87.7816,"start":222,"end":416}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01011","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01011-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01011-F1-predicted_aligned_error_v6.png","plddt_mean":85.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SERPINA3","jax_strain_url":"https://www.jax.org/strain/search?query=SERPINA3"},"sequence":{"accession":"P01011","fasta_url":"https://rest.uniprot.org/uniprotkb/P01011.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01011/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01011"}},"corpus_meta":[{"pmid":"12045112","id":"PMC_12045112","title":"RNA 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pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"SERPINA3 (alpha-1-antichymotrypsin/ACT) functions as a serine protease inhibitor; its structure, regulatory elements, tissue-specific expression, and physiological roles including acute-phase response were characterized. It inhibits cathepsin G and other serine proteases.\",\n      \"method\": \"Review synthesizing proteomic, transcriptomic, and genomic studies\",\n      \"journal\": \"Frontiers in bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — comprehensive review consolidating prior experimental work; no single new experiment described\",\n      \"pmids\": [\"17485262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SERPINA3 (serpina3) is expressed by multiple hematopoietic cell populations in bone marrow and is down-regulated at both mRNA and protein levels during G-CSF- or chemotherapy-induced hematopoietic progenitor mobilization, shifting the balance between serine protease inhibitors and neutrophil serine proteases to allow progenitor release.\",\n      \"method\": \"Protein and mRNA expression analysis (ELISA, RT-PCR) in bone marrow during mobilization; tissue comparison (bone marrow vs. liver)\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — orthogonal methods (protein and mRNA), functional context established via tissue-specific expression changes\",\n      \"pmids\": [\"15795238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Orphan nuclear receptor Nur77 directly binds to the NBRE element (-182 to -175) in the SERPINA3 promoter, transactivating SERPINA3 gene expression, as demonstrated by EMSA, ChIP, luciferase reporter assays, Nur77 overexpression, and RNA interference-mediated knockdown.\",\n      \"method\": \"Luciferase reporter assay, EMSA, chromatin immunoprecipitation (ChIP), Nur77 overexpression, RNA interference knockdown\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (reporter assay, EMSA, ChIP, gain/loss of function) in single study\",\n      \"pmids\": [\"18248459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ApoA4 stimulates SERPINA3 gene expression in mouse hepatocytes in a dose- and time-dependent manner; the transcriptional response is mediated by ApoA4 binding to nuclear receptors NR4A1 and NR1D1 on the SERPINA3 promoter, as confirmed by ChIP, luciferase assay, and RNA interference of NR4A1 or NR1D1.\",\n      \"method\": \"ChIP, luciferase reporter assay, RNA interference, RT-PCR, in vivo and in vitro hepatocyte stimulation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (ChIP, reporter assay, RNAi) in single study confirming promoter binding and transcriptional regulation\",\n      \"pmids\": [\"28412351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"STAT3 directly regulates SERPINA3 transcription in human melanoma cells; STAT3 knockdown reduces SERPINA3 expression, and STAT3 physically associates with defined STAT3-binding sites in the SERPINA3 promoter as validated by ChIP-qPCR. SERPINA3 is functionally involved in STAT3-mediated regulation of melanoma migration and invasion.\",\n      \"method\": \"Gene expression profiling, STAT3 siRNA knockdown, chromatin immunoprecipitation (ChIP)-qPCR, migration and invasion assays\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal epistasis (STAT3 KD reduces SERPINA3), direct promoter binding by ChIP, functional readout (migration/invasion)\",\n      \"pmids\": [\"31278347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SERPINA3 promotes endometrial cancer cell proliferation by regulating G2/M cell cycle checkpoint and inhibiting apoptosis; this pro-proliferative effect is mediated through activation of MAPK/ERK1/2 and PI3K/AKT signaling pathways.\",\n      \"method\": \"SERPINA3 overexpression/knockdown, cell cycle analysis, apoptosis assay, western blot for ERK1/2 and AKT phosphorylation\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gain/loss of function with pathway analysis by western blot; single lab\",\n      \"pmids\": [\"24817931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SERPINA3 silencing inhibits the migration, invasion, and liver metastasis of colon cancer cells, and reduces MMP-2 and MMP-9 expression levels both in vitro (ELISA) and in vivo (immunohistochemistry in mouse liver metastasis model).\",\n      \"method\": \"siRNA knockdown, wound-healing assay, Transwell invasion assay, ELISA (MMP-2/9), mouse xenograft liver metastasis model, immunohistochemistry\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo loss-of-function with mechanistic link to MMP-2/9\",\n      \"pmids\": [\"29855767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SERPINA3 knockdown significantly decreases migration and matrix invasion of melanoma cells without affecting proliferation, establishing a pro-migration and pro-invasion function for SERPINA3 in melanoma.\",\n      \"method\": \"siRNA knockdown, cell migration assay, matrix invasion assay, cell proliferation assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — specific loss-of-function with defined cellular phenotype readouts\",\n      \"pmids\": [\"27213583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SERPINA3 overexpression in triple-negative breast cancer cells promotes cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) by upregulating EMT markers and EZH2; SERPINA3 overexpression also reduces sensitivity to cisplatin.\",\n      \"method\": \"Overexpression and knockdown, wound healing, Transwell assay, CCK-8 proliferation assay, western blot for EMT markers and EZH2, drug sensitivity assay\",\n      \"journal\": \"Breast cancer (Tokyo, Japan)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — gain and loss of function with EMT marker analysis; single lab\",\n      \"pmids\": [\"33569740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SERPINA3 regulates vascular smooth muscle cell (VSMC) proliferation and migration through the NF-κB signaling pathway; SERPINA3 knockdown in rat aortic smooth muscle cells attenuated proliferation, migration, and inhibited phosphorylated IκBα and its downstream pathway. Secreted SERPINA3 protein increases inflammatory factor expression in human umbilical vein endothelial cells (HUVECs).\",\n      \"method\": \"siRNA knockdown in RASMCs, EdU proliferation assay, scratch migration assay, western blot and RT-PCR for NF-κB pathway components, SERPINA3 protein stimulation of HUVECs\",\n      \"journal\": \"Frontiers in cardiovascular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — loss-of-function with pathway analysis; in vitro only; single lab\",\n      \"pmids\": [\"34957248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CircSERPINA3 stabilizes SERPINA3 mRNA by recruiting the RNA-binding protein BUD13, and also acts as a miR-653-5p sponge to competitively release SERPINA3 from miR-653-5p-mediated suppression. SERPINA3 itself inhibits apoptosis and promotes aerobic glycolysis and autophagy in prostate cancer cells.\",\n      \"method\": \"RT-qPCR, RNA pulldown, luciferase reporter assay (miRNA sponge), RIP (RNA immunoprecipitation), functional assays (apoptosis, autophagy, glycolysis)\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple mechanism assays (RIP, reporter, functional) in single lab\",\n      \"pmids\": [\"34861864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SERPINA3 overexpression in lung cancer cells upregulates SPOP and inhibits NF-κB p65, suppressing tumor cell growth, proliferation, migration, and invasion; mechanistically identified by data-independent acquisition mass spectrometry (DIA-MS) and validated by western blot in cell lines and mouse xenograft tumors.\",\n      \"method\": \"SERPINA3 overexpression, DIA-MS proteomics, western blot, xenograft mouse model, proliferation and invasion assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomic discovery + in vitro and in vivo validation of SPOP/NF-κB mechanism\",\n      \"pmids\": [\"37417362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Human SERPINA3 overexpression in mice induces neocortical folding and increases outer radial glia (oRG) proliferation and upper-layer neuron numbers; SERPINA3 promotes oRG proliferation by binding to the Glo1 promoter, with Glo1 identified as a downstream target involved in SERPINA3-induced gyrification.\",\n      \"method\": \"SERPINA3 overexpression in mouse brain, ChIP (SERPINA3 binding to Glo1 promoter), histological analysis, behavioral cognitive testing\",\n      \"journal\": \"Cell discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct promoter binding; in vivo gain-of-function with defined cellular and behavioral phenotypes\",\n      \"pmids\": [\"36414636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SERPINA3 inhibits NF-κB activation and downstream inflammatory mediators (COX2, iNOS, TNF-α, IL-6, MMP13, MMP9) in osteoarthritis chondrocytes; sinensetin exerts its chondroprotective effects partly by regulating SERPINA3 expression.\",\n      \"method\": \"In vitro IL-1β-stimulated OA chondrocytes, siRNA/pharmacological modulation of SERPINA3, western blot for NF-κB and inflammatory markers, rat OA in vivo model\",\n      \"journal\": \"Food & function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic link between SERPINA3 and NF-κB in vitro and in vivo; single lab\",\n      \"pmids\": [\"36056701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SERPINA3 is strongly up-regulated at both mRNA and protein levels in the brain of all human prion disease subtypes, suggesting involvement in prion disease pathogenesis and progression; this is distinct from the mild up-regulation observed in Alzheimer's disease.\",\n      \"method\": \"RT-qPCR on frontal cortex samples (128 prion disease patients, 14 AD patients, 30 controls), protein-level confirmation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression analysis without direct mechanistic experiment; included as it provides molecular context for pathogenic role\",\n      \"pmids\": [\"29142239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SERPINA3 is upregulated in renal tubules of diabetic nephropathy patients; as an inhibitor of mast cell chymase, SERPINA3 is proposed to protect against renal tubular injury by inhibiting mast cell proliferation/activation and chymase activity.\",\n      \"method\": \"RNA-seq dataset analysis, immunohistochemistry of human renal tubular biopsies for SERPINA3 and chymase expression, mast cell infiltration analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — expression-based with prior biochemical knowledge of serine protease inhibitory function; no direct functional experiment on chymase inhibition reported here\",\n      \"pmids\": [\"36304455\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SERPINA3 (alpha-1-antichymotrypsin) is a serine protease inhibitor (targeting cathepsin G, chymase, and related proteases) secreted as an acute-phase protein primarily by the liver; its transcription is directly regulated by nuclear receptors Nur77, NR4A1/NR1D1 (via ApoA4), and STAT3; in cancer cells it modulates migration, invasion, and EMT partly through MMP-2/9 regulation, MAPK/ERK and PI3K/AKT signaling, SPOP/NF-κB pathways, and EZH2 upregulation; in the CNS it promotes outer radial glia proliferation and cortical folding via binding to the Glo1 promoter; and in the bone marrow it regulates the protease–antiprotease balance governing hematopoietic progenitor mobilization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SERPINA3 (alpha-1-antichymotrypsin) is a secreted serine protease inhibitor that functions as an acute-phase protein, inhibiting cathepsin G and related proteases, and participates in diverse processes including hematopoietic progenitor mobilization, inflammation, cortical development, and cancer progression [PMID:17485262, PMID:15795238]. Its transcription is directly regulated by the orphan nuclear receptor Nur77 via an NBRE element in the promoter, by NR4A1/NR1D1 in response to ApoA4 signaling in hepatocytes, and by STAT3 in melanoma cells [PMID:18248459, PMID:28412351, PMID:31278347]. In multiple cancer types, SERPINA3 promotes cell proliferation, migration, invasion, and epithelial-mesenchymal transition through MAPK/ERK, PI3K/AKT, NF-κB, and EZH2-dependent mechanisms, and facilitates metastasis partly by upregulating MMP-2/9 [PMID:24817931, PMID:29855767, PMID:33569740, PMID:37417362]. In the developing brain, SERPINA3 overexpression drives outer radial glia proliferation and neocortical gyrification by binding the Glo1 promoter [PMID:36414636].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that SERPINA3 is not merely a hepatic acute-phase protein but is expressed by bone marrow hematopoietic cells and dynamically down-regulated during progenitor mobilization, linking protease–antiprotease balance to stem cell release.\",\n      \"evidence\": \"ELISA and RT-PCR of bone marrow during G-CSF- or chemotherapy-induced mobilization in human subjects\",\n      \"pmids\": [\"15795238\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration that SERPINA3 loss is required or sufficient for progenitor egress\",\n        \"Identity of the specific serine protease(s) counterbalanced by SERPINA3 in this context not established\",\n        \"Mechanism of SERPINA3 down-regulation during mobilization unknown\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying the first direct transcriptional regulator of SERPINA3: the orphan nuclear receptor Nur77 binds an NBRE element at −182 to −175 in the SERPINA3 promoter, explaining how nuclear receptor signaling controls acute-phase SERPINA3 expression.\",\n      \"evidence\": \"EMSA, ChIP, luciferase reporter, Nur77 overexpression and RNAi in human cell lines\",\n      \"pmids\": [\"18248459\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological stimuli upstream of Nur77 that regulate SERPINA3 in vivo not defined\",\n        \"Contribution of Nur77 versus other transcription factors to hepatic SERPINA3 expression not quantified\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that SERPINA3 has a cell-autonomous pro-proliferative role in cancer, promoting G2/M progression and inhibiting apoptosis via MAPK/ERK1/2 and PI3K/AKT signaling — shifting understanding from a secreted protease inhibitor to an intracellular signaling modulator.\",\n      \"evidence\": \"SERPINA3 overexpression/knockdown in endometrial cancer cells with cell cycle, apoptosis, and phospho-western blot readouts\",\n      \"pmids\": [\"24817931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding partners mediating MAPK/ERK and PI3K/AKT activation not identified\",\n        \"Whether the protease inhibitory activity is required for the proliferative phenotype is unknown\",\n        \"Findings limited to a single cancer type at this point\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extending SERPINA3's oncogenic role to melanoma (pro-migration/invasion without affecting proliferation) and showing that ApoA4-NR4A1/NR1D1 signaling constitutes a second nuclear-receptor-dependent transcriptional axis for SERPINA3 in hepatocytes, broadening understanding of its regulation.\",\n      \"evidence\": \"siRNA knockdown with migration/invasion assays in melanoma (PMID:27213583); ChIP, luciferase, and RNAi for NR4A1/NR1D1 in mouse hepatocytes (PMID:28412351)\",\n      \"pmids\": [\"27213583\", \"28412351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The cell-type-specific effects (proliferation vs. migration) are unexplained mechanistically\",\n        \"Whether NR4A1/NR1D1-mediated regulation occurs in extrahepatic tissues is untested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Providing in vivo evidence that SERPINA3 promotes cancer metastasis: silencing SERPINA3 reduces colon cancer liver metastasis in a mouse xenograft model, mechanistically linked to decreased MMP-2/9 expression.\",\n      \"evidence\": \"siRNA knockdown, Transwell invasion assay, ELISA for MMP-2/9, mouse liver metastasis model with IHC\",\n      \"pmids\": [\"29855767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MMP-2/9 regulation by SERPINA3 is direct or indirect remains unresolved\",\n        \"Role of SERPINA3's protease inhibitory function versus a non-canonical activity in metastasis is unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying STAT3 as a third direct transcriptional regulator of SERPINA3, binding defined sites in the SERPINA3 promoter in melanoma cells and coupling SERPINA3 expression to STAT3-driven migration and invasion.\",\n      \"evidence\": \"STAT3 siRNA knockdown, ChIP-qPCR for STAT3 at SERPINA3 promoter, migration and invasion assays in melanoma cells\",\n      \"pmids\": [\"31278347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether STAT3 regulation of SERPINA3 generalizes beyond melanoma is unknown\",\n        \"Epistatic relationship between Nur77 and STAT3 at the SERPINA3 promoter not addressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadening SERPINA3's downstream signaling repertoire: in breast cancer SERPINA3 drives EMT through EZH2 upregulation and reduces cisplatin sensitivity; in vascular smooth muscle cells it promotes proliferation and migration via NF-κB/IκBα phosphorylation; and circSERPINA3 stabilizes SERPINA3 mRNA through BUD13 recruitment and miR-653-5p sponging.\",\n      \"evidence\": \"Overexpression/knockdown with EMT marker and EZH2 western blot in TNBC (PMID:33569740); siRNA in RASMCs with NF-κB western blot (PMID:34957248); RIP, RNA pulldown, luciferase reporter for circSERPINA3/BUD13/miR-653-5p axis in prostate cancer (PMID:34861864)\",\n      \"pmids\": [\"33569740\", \"34957248\", \"34861864\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether EZH2 is a direct or indirect target of SERPINA3 is unknown\",\n        \"The NF-κB effects of SERPINA3 differ in direction across cancer vs. vascular contexts — mechanistic basis unresolved\",\n        \"All findings from single labs without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing a neurodevelopmental role: human SERPINA3 overexpression in mouse brain induces cortical folding by promoting outer radial glia proliferation, with SERPINA3 directly binding the Glo1 promoter as a transcriptional mechanism — an unexpected non-canonical function for a serpin.\",\n      \"evidence\": \"In vivo SERPINA3 overexpression in mouse brain, ChIP for SERPINA3 at Glo1 promoter, histological and behavioral analysis\",\n      \"pmids\": [\"36414636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How a secreted protease inhibitor enters the nucleus and acts as a transcriptional regulator is mechanistically unexplained\",\n        \"Whether endogenous SERPINA3 is required for human cortical gyrification is untested\",\n        \"Glo1 downstream effectors mediating oRG proliferation not identified\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that SERPINA3 modulates NF-κB-dependent inflammation in osteoarthritis chondrocytes, suppressing COX2, iNOS, TNF-α, IL-6, and MMPs — consistent with its anti-inflammatory function via protease inhibition in non-cancer contexts.\",\n      \"evidence\": \"siRNA and pharmacological modulation in IL-1β-stimulated chondrocytes with NF-κB western blot; rat OA model\",\n      \"pmids\": [\"36056701\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether chondroprotective effects require serine protease inhibitory activity specifically is not tested\",\n        \"Findings from a single lab; effect size of SERPINA3 relative to other serpins in OA unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"In lung cancer, SERPINA3 overexpression upregulates SPOP and suppresses NF-κB p65, inhibiting tumor growth — revealing context-dependent tumor-suppressive activity contrasting with its oncogenic role in other cancers.\",\n      \"evidence\": \"DIA-MS proteomics, western blot validation, xenograft mouse model with SERPINA3 overexpression in lung cancer cells\",\n      \"pmids\": [\"37417362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Why SERPINA3 is tumor-suppressive in lung cancer but oncogenic in other cancers is mechanistically unexplained\",\n        \"Whether SERPINA3 directly regulates SPOP expression or acts indirectly is not established\",\n        \"Single study; independent replication lacking\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major open questions remain: (1) how a secreted serpin accesses the nucleus to regulate promoters (Glo1), (2) what determines the context-dependent pro- vs. anti-tumorigenic activity across cancer types, and (3) whether the protease-inhibitory and signaling functions are mechanistically separable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No nuclear import mechanism or nuclear localization signal identified for SERPINA3\",\n        \"Structure–function dissection separating protease inhibition from intracellular signaling not performed\",\n        \"No crystal structure of SERPINA3 bound to a non-protease partner\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [0, 1, 6, 13, 15]\n      },\n      {\n        \"term_id\": \"GO:0140110\",\n        \"supporting_discovery_ids\": [12]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005576\",\n        \"supporting_discovery_ids\": [0, 1, 9]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0162582\",\n        \"supporting_discovery_ids\": []\n      },\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [1, 13]\n      },\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [5, 9, 11]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NR4A1\",\n      \"NR1D1\",\n      \"STAT3\",\n      \"SPOP\",\n      \"EZH2\",\n      \"BUD13\",\n      \"GLO1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}