{"gene":"ALB","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1989,"finding":"The three-dimensional structure of human serum albumin was solved at 6.0 Å resolution by multiple isomorphous replacement, revealing a predominantly alpha-helical protein and identifying binding loci for several organic compounds.","method":"X-ray crystallography (multiple isomorphous replacement)","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — original crystal structure determination, foundational structural paper","pmids":["2727704"],"is_preprint":false},{"year":1992,"finding":"The atomic structure of human serum albumin was determined at 2.8 Å resolution, revealing three homologous domains assembling into a heart-shaped molecule, with principal ligand-binding regions located in hydrophobic cavities in subdomains IIA and IIIA that exhibit similar chemistry.","method":"X-ray crystallography","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure with functional site identification, >2500 citations","pmids":["1630489"],"is_preprint":false},{"year":1998,"finding":"Crystal structure of HSA complexed with five molecules of myristate at 2.5 Å resolution revealed that fatty acids bind in long hydrophobic pockets capped by polar (often basic) side chains, and that these pockets are distributed asymmetrically throughout the molecule despite its symmetrical repeating domain structure.","method":"X-ray crystallography","journal":"Nature structural biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution co-crystal structure defining fatty acid binding sites, >1000 citations","pmids":["9731778"],"is_preprint":false},{"year":1999,"finding":"A new triclinic crystal form of HSA at 2.5 Å resolution confirmed that Cys34 is the only free sulfhydryl group not in a disulfide bond, and showed that domains II and III both contain hydrophobic, positively charged pockets capable of accommodating a wide range of compounds; three tentative fatty acid binding sites were identified at domain surfaces.","method":"X-ray crystallography (molecular replacement)","journal":"Protein engineering","confidence":"High","confidence_rationale":"Tier 1 — independent high-resolution crystal structure replicating and extending prior structural findings","pmids":["10388840"],"is_preprint":false},{"year":2000,"finding":"High-resolution crystal structures of HSA complexed with the general anesthetics propofol and halothane showed that propofol binds at two discrete sites and halothane at three sites (at pharmacologically relevant concentrations), all of which are fatty acid binding loci; binding causes only minor local structural changes.","method":"X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — co-crystal structures of drug–albumin complexes at high resolution, >400 citations","pmids":["10940303"],"is_preprint":false},{"year":2003,"finding":"The neonatal Fc receptor FcRn was shown to bind albumin in a pH-dependent manner; FcRn-deficient mice had shortened albumin lifespan and plasma albumin concentrations less than half those of wild-type mice, demonstrating that FcRn protects albumin from degradation and prolongs its half-life.","method":"pH-dependent binding assay; FcRn knockout mouse model with pharmacokinetic measurements","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — direct binding assay plus genetic loss-of-function with quantitative pharmacokinetic readout, >500 citations","pmids":["12566415"],"is_preprint":false},{"year":2005,"finding":"Crystallographic analysis of 17 HSA–drug complexes identified the precise architecture of two primary drug-binding sites (Sudlow sites I and II in subdomains IIA and IIIA), key residues determining binding specificity, and numerous secondary binding sites; fatty acid binding was shown to alter the polarity and increase the volume of drug site 1.","method":"X-ray crystallography (17 co-crystal structures)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — systematic co-crystal structure series with multiple ligands and functional interpretation, >1300 citations","pmids":["16169013"],"is_preprint":false},{"year":2005,"finding":"Human plasma albumin was demonstrated to possess esterase activity toward alpha- and beta-naphthylacetate and p-nitrophenyl acetate, as shown by nondenaturing gradient gel electrophoresis with esterase activity staining; human plasma was also shown to lack carboxylesterase activity entirely.","method":"Nondenaturing gradient gel electrophoresis with esterase activity staining; enzyme kinetics","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with direct protein identification, replicated across species, >400 citations","pmids":["16213467"],"is_preprint":false},{"year":2008,"finding":"Albumin's antioxidant properties were characterized, including its roles in ligand binding and free radical trapping; the single free thiol at Cys34 was identified as the principal site of free radical scavenging activity, and glycation and oxidative modifications were shown to alter these antioxidant functions.","method":"Review integrating in vitro oxidative stress assays and biochemical characterization","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — synthesis of multiple experimental studies; antioxidant mechanism at Cys34 supported by multiple labs","pmids":["18474236"],"is_preprint":false},{"year":2024,"finding":"Reduced/thiol-active albumin (SH-Alb) was shown to inhibit pro-fibrotic macrophage phenotype remodeling through the SIRT3–SOD2 axis: SH-Alb promoted SIRT3 expression, which deacetylated SOD2 (a key mitochondrial ROS-producing enzyme), reducing ROS accumulation; SH-Alb also reduced pro-inflammatory/pro-fibrotic cytokine release via the MAPK signaling pathway, and macrophages altered by SH-Alb inhibited hepatic stellate cell and endothelial cell activation.","method":"In vivo mouse liver fibrosis model; in vitro macrophage assays; Western blot; MAPK pathway inhibition","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro and in vivo assays with defined pathway (SIRT3-SOD2/MAPK) by single lab","pmids":["38876053"],"is_preprint":false},{"year":2023,"finding":"WTAP was shown to suppress ALB expression in osteosarcoma cells in an m6A-dependent manner: WTAP knockdown increased ALB mRNA and protein levels, Me-RIP and dual luciferase reporter assays confirmed WTAP targets ALB mRNA via m6A modification, and ALB knockdown reversed the anti-tumor effects of WTAP silencing on cell viability, migration, and invasion.","method":"Me-RIP; dual luciferase reporter assay; m6A quantification; siRNA knockdown; CCK-8, wound healing, and transwell invasion assays; xenograft mouse model","journal":"Environmental toxicology / Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — m6A writer-target relationship validated by Me-RIP and reporter assay plus functional rescue, single lab","pmids":["36988233","36690262"],"is_preprint":false},{"year":2025,"finding":"ALB overexpression in clear cell renal cell carcinoma (ccRCC) cells suppressed proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), activated endoplasmic reticulum stress (ERS) in vitro and in vivo, and was causally associated with γδT cell infiltration; mechanistically, ALB showed a negative association with SPARC, which was identified as a potential mediator of EMT downstream of ALB.","method":"ALB overexpression/knockdown in ccRCC cell lines; xenograft tumor model; Mendelian randomization (GWAS-based causal inference); functional assays (proliferation, migration, invasion); Western blot; ERS marker assessment","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 — single lab, ALB–SPARC association inferred rather than mechanistically demonstrated; ERS activation shown in vitro/vivo but pathway mechanism not fully resolved","pmids":["39862995"],"is_preprint":false},{"year":2026,"finding":"ALB overexpression in metastatic ccRCC cell lines suppressed proliferation, EMT, and glycolytic activity (reduced glycolytic intermediates, glucose uptake, and lactate production as measured by Seahorse metabolic flux analysis); silencing SPARC or inhibiting glycolysis reversed the malignant phenotypes induced by ALB knockdown, placing SPARC as a downstream effector through which ALB regulates EMT and glycolysis.","method":"ALB overexpression/knockdown; Seahorse glycolytic flux analysis; SPARC knockdown; transwell/migration assays; Western blot; metabolomic analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 — single lab, functional link between ALB, SPARC, and glycolysis supported by rescue experiments but mechanistic details of ALB–SPARC interaction not biochemically defined","pmids":["41610717"],"is_preprint":false},{"year":2017,"finding":"Heterozygous gain-of-function variants in the ALB gene (including p.Arg242His) cause familial dysalbuminemic hyperthyroxinemia (FDH) by producing an albumin variant with altered thyroid hormone-binding affinity, leading to elevated circulating total T4 with normal physiological thyroid function; ALB hotspot sequencing was validated as the definitive diagnostic method.","method":"Sanger sequencing of ALB gene; protein structure analysis; thyroid function testing across family members","journal":"Annals of laboratory medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct genotype–phenotype linkage with family segregation and structural interpretation; replicated in multiple subsequent case reports","pmids":["27834068"],"is_preprint":false},{"year":2010,"finding":"Analysis of bisalbuminemia in Korean patients identified ALB gene variants (including a novel Lys198Ile missense mutation) and showed that the mutation sites were not located within known protein-binding loci; 3D structural modeling confirmed that these variants alter albumin electrophoretic mobility without affecting binding affinity for common biochemical compounds.","method":"Serum protein electrophoresis; Sanger sequencing; 3D molecular modeling of albumin variants","journal":"The Korean journal of laboratory medicine","confidence":"Low","confidence_rationale":"Tier 3 — structural modeling rather than direct biochemical binding assay; single-lab case report","pmids":["20603593"],"is_preprint":false}],"current_model":"Human serum albumin (ALB) is a three-domain, predominantly alpha-helical plasma protein whose crystal structures have precisely defined two primary drug-binding sites (Sudlow sites I and II in subdomains IIA and IIIA) and multiple fatty acid-binding pockets distributed asymmetrically across the molecule; its long plasma half-life is maintained by pH-dependent binding to FcRn, which rescues it from lysosomal degradation; it possesses intrinsic esterase activity and antioxidant activity centered on the free thiol at Cys34; its thiol redox state (SH-Alb) modulates macrophage phenotype through the SIRT3–SOD2 axis and MAPK signaling; and its expression is post-transcriptionally suppressed by the m6A writer WTAP in osteosarcoma, with gain-of-function variants in ALB causing familial dysalbuminemic hyperthyroxinemia by altering thyroid hormone-binding affinity."},"narrative":{"teleology":[],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]},"mechanistic_narrative":"Insufficient on-target evidence to synthesize a narrative — discovery timeline does not match the canonical ALB protein."},"prefetch_data":{"uniprot":{"accession":"P02768","full_name":"Albumin","aliases":[],"length_aa":609,"mass_kda":69.4,"function":"Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P02768/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ALB","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ALB","total_profiled":1310},"omim":[{"mim_id":"619504","title":"CHOPRA-AMIEL-GORDON SYNDROME; CAGS","url":"https://www.omim.org/entry/619504"},{"mim_id":"618882","title":"IMERSLUND-GRASBECK SYNDROME 2; IGS2","url":"https://www.omim.org/entry/618882"},{"mim_id":"616807","title":"FAS-BINDING FACTOR 1; FBF1","url":"https://www.omim.org/entry/616807"},{"mim_id":"616000","title":"ANALBUMINEMIA; ANALBA","url":"https://www.omim.org/entry/616000"},{"mim_id":"615999","title":"HYPERTHYROXINEMIA, FAMILIAL DYSALBUMINEMIC; FDAH","url":"https://www.omim.org/entry/615999"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":198523.8}],"url":"https://www.proteinatlas.org/search/ALB"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8TES7","domains":[{"cath_id":"1.20.5","chopping":"578-735","consensus_level":"high","plddt":94.4742,"start":578,"end":735}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TES7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TES7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TES7-F1-predicted_aligned_error_v6.png","plddt_mean":62.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ALB","jax_strain_url":"https://www.jax.org/strain/search?query=ALB"},"sequence":{"accession":"Q8TES7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TES7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TES7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TES7"}},"corpus_meta":[{"pmid":"19242562","id":"PMC_19242562","title":"HCV induces 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genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23535732","citation_count":463,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22286219","id":"PMC_22286219","title":"Genome-wide association study identifies multiple loci influencing human serum metabolite levels.","date":"2012","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22286219","citation_count":436,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16213467","id":"PMC_16213467","title":"Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma.","date":"2005","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/16213467","citation_count":421,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10940303","id":"PMC_10940303","title":"Binding of the general anesthetics propofol and halothane to human serum albumin. High resolution crystal structures.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10940303","citation_count":414,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2727704","id":"PMC_2727704","title":"Three-dimensional structure of human serum albumin.","date":"1989","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/2727704","citation_count":395,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15324660","id":"PMC_15324660","title":"Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization.","date":"2004","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/15324660","citation_count":386,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8132774","id":"PMC_8132774","title":"Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter.","date":"1994","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/8132774","citation_count":378,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":43372,"output_tokens":2276,"usd":0.082128},"stage2":{"model":"claude-opus-4-6","input_tokens":5579,"output_tokens":1905,"usd":0.11328},"total_usd":0.365978,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":55613,"output_tokens":4009,"usd":0.113487},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7091,"output_tokens":104,"usd":0.057083}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"A long noncoding RNA named ALB (lncRNA ALB) was identified that regulates autophagy in human lens development by enhancing the conversion of LC3BI to LC3BII; knockdown of lncRNA ALB reduced LC3BII protein levels and inhibited autophagy in human lens epithelial cells.\",\n      \"method\": \"lncRNA knockdown (siRNA) with Western blot for LC3BII, expression profiling in differentiating lentoid bodies and human embryonic lenses\",\n      \"journal\": \"Molecular therapy. Nucleic acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined molecular phenotype (LC3BII reduction), single lab, single method\",\n      \"pmids\": [\"29246299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ALB gene variants (e.g., Nagasaki-1/Asp293Gly; novel Lys198Ile) cause bisalbuminemia with altered electrophoretic mobility; 3D structural modeling showed mutation sites are not located at protein-binding loci, predicting no effect on albumin-binding affinity for biochemical compounds, which was confirmed by unchanged serum concentrations of albumin-bound substances.\",\n      \"method\": \"Sanger sequencing of ALB gene, serum protein electrophoresis, 3D structural modeling\",\n      \"journal\": \"The Korean journal of laboratory medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — genetic/structural analysis without in vitro binding reconstitution; single lab\",\n      \"pmids\": [\"20603593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by heterozygous gain-of-function variants in the ALB gene (e.g., p.Arg242His/p.Arg242Pro), which alter albumin's binding affinity for thyroxine (T4), leading to elevated circulating total T4 with normal physiological thyroid function; different immunoassay methods give discordant free T4 results due to the variant albumin.\",\n      \"method\": \"Sanger sequencing of ALB gene, thyroid function testing with multiple immunoassay platforms, family segregation analysis\",\n      \"journal\": \"Annals of laboratory medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional consequence (altered T4 binding) demonstrated by differential immunoassay behavior; replicated in multiple FDH reports\",\n      \"pmids\": [\"27834068\", \"34142517\", \"38736368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WTAP, an m6A methyltransferase adaptor, modulates ALB mRNA expression in an m6A-dependent manner in osteosarcoma cells; Me-RIP and dual luciferase reporter assays confirmed WTAP targets the ALB transcript, and silencing WTAP increased ALB levels, reducing osteosarcoma cell viability, migration, and invasion, while ALB knockdown reversed these effects.\",\n      \"method\": \"Me-RIP assay, dual luciferase reporter assay, m6A quantification assay, mRNA stability assay, CCK-8, wound healing, transwell invasion, xenograft mouse model\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Me-RIP, reporter assay, mRNA stability) demonstrating m6A-dependent regulation; single lab\",\n      \"pmids\": [\"36988233\", \"36690262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Reduced thiol-modified albumin (SH-Alb) inhibits macrophage pro-fibrotic phenotype remodeling by reducing MAPK signaling-mediated cytokine release and by promoting SIRT3 expression, which deacetylates SOD2 (a key mitochondrial ROS enzyme), thereby reducing ROS accumulation and attenuating liver fibrosis.\",\n      \"method\": \"In vivo mouse liver fibrosis model (in vivo/in vitro), Western blot, MAPK pathway analysis, SIRT3/SOD2 deacetylation assay, hepatic stellate cell and endothelial cell co-culture\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanism (SIRT3-SOD2 axis) supported by multiple biochemical assays; single lab\",\n      \"pmids\": [\"38876053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ccRCC cells, ALB overexpression suppressed epithelial-mesenchymal transition (EMT) and glycolysis through a negative association with SPARC; ALB overexpression reduced glycolytic intermediates, glucose uptake, and lactate production, and these malignant phenotypes were reversed by glycolysis inhibition or SPARC knockdown.\",\n      \"method\": \"Functional assays (proliferation, transwell, Western blot), Seahorse metabolic flux analysis, metabolomics, SPARC knockdown rescue experiments in ccRCC cell lines\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with rescue experiment; single lab\",\n      \"pmids\": [\"41610717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALB overexpression in ccRCC activated endoplasmic reticulum stress (ERS) in vitro and in vivo, and was causally associated with γδT cell infiltration in ccRCC by Mendelian randomization analysis; ALB knockdown increased cell proliferation, migration, and invasion.\",\n      \"method\": \"ALB overexpression/knockdown in ccRCC cell lines, in vivo xenograft, ERS pathway analysis, Mendelian randomization (GWAS-based)\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional assays with ERS pathway, but Mendelian randomization is associative; single lab\",\n      \"pmids\": [\"39862995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1982,\n      \"finding\": \"Immunocytochemical localization of serum albumin (ALB) in rat fetal tissues showed transitory intracellular presence of ALB in derivatives of all three germ layers during development, with labeling following the stage of cell and tissue differentiation and appearing ~2–5 days later than AFP labeling.\",\n      \"method\": \"Immunocytochemistry on rat fetal and neonatal tissues across developmental time points\",\n      \"journal\": \"Oncodevelopmental biology and medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization study without direct functional consequence established\",\n      \"pmids\": [\"6181479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"RGD peptide conjugated to albumin (RGD-ALB) promoted endothelial cell adhesion, spreading, migration, and growth on coated surfaces, demonstrating that albumin can serve as a carrier scaffold for bioactive adhesion peptides with functional cellular responses comparable to fibronectin.\",\n      \"method\": \"Carbodiimide coupling of GRGDS to albumin; bovine endothelial cell adhesion, spreading, proliferation and migration assays on coated surfaces; comparison to fibronectin and vitronectin\",\n      \"journal\": \"ASAIO journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — in vitro functional assay; single lab, engineering/conjugate study rather than endogenous mechanism\",\n      \"pmids\": [\"1457864\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human serum albumin (ALB) is a hepatocyte-secreted plasma protein whose variants (e.g., Arg242His/Pro) cause altered thyroxine-binding affinity leading to familial dysalbuminemic hyperthyroxinemia; its expression is regulated post-transcriptionally via WTAP-mediated m6A modification of ALB mRNA; in tumor contexts ALB suppresses EMT and glycolysis through SPARC downregulation and activates endoplasmic reticulum stress; a lncRNA sharing the symbol ALB regulates autophagy by promoting LC3BI-to-LC3BII conversion in lens development; and reduced-thiol albumin (SH-Alb) attenuates liver fibrosis via the SIRT3-SOD2 axis in macrophages.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nFrom the retrieved 84 papers:\n- Papers about human serum albumin (ALB protein): KEEP — papers [12], [29], [43], [51], [67], [75], [60], [45], [63], [42], [81], [61], [71] (partially - Alb as mouse protein)\n- Papers about Alb-uPA/SCID mouse models (using albumin promoter as a tool): These use ALB promoter but don't describe ALB protein mechanism — EXCLUDE for mechanistic findings\n- Papers about Bacillus subtilis sbo-alb locus: EXCLUDE (symbol collision — bacterial genes)\n- Papers about Alb-PRF (albumin-platelet rich fibrin): These involve albumin as a material/scaffold — limited mechanistic content about ALB protein itself\n- Paper [26] (lncRNA ALB): EXCLUDE — alt-locus product (case B)\n- Paper [2] from Bacillus subtilis: EXCLUDE\n- Mo2AlB2 chemistry paper [9]: EXCLUDE\n- Aplysia Alb-1 [28]: EXCLUDE (symbol collision — different organism/protein)\n- dt-Alb mice [20]: EXCLUDE — about BPAG1/dystonin gene, not ALB\n- Various clinical ratio papers (CRP/ALB, RDW/ALB): EXCLUDE — biomarker/prognostic only\n- Paper [60] SH-Alb: KEEP — describes ALB thiol activity mechanism in macrophage phenotype\n\nFrom gene2pubmed curated papers:\n- [1] Crystal structure HSA: KEEP\n- [4] Drug binding specificity crystal structures: KEEP\n- [6] Crystal structure HSA 2.5Å: KEEP\n- [9] Crystal structure fatty acid binding: KEEP\n- [11] Antioxidant properties: KEEP\n- [19] FcRn binds albumin: KEEP\n- [25] Albumin esterase activity: KEEP\n- [26] Propofol/halothane binding crystal structures: KEEP\n- [28] 3D structure 6Å: KEEP\n- [2], [3], [5], [7], [8], [10], [12]–[18], [20]–[24], [27], [29], [30]: Interactome/proteome screens, GWAS, transporter papers — not specifically about ALB mechanism → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1989,\n      \"finding\": \"The three-dimensional structure of human serum albumin was solved at 6.0 Å resolution by multiple isomorphous replacement, revealing a predominantly alpha-helical protein and identifying binding loci for several organic compounds.\",\n      \"method\": \"X-ray crystallography (multiple isomorphous replacement)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original crystal structure determination, foundational structural paper\",\n      \"pmids\": [\"2727704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The atomic structure of human serum albumin was determined at 2.8 Å resolution, revealing three homologous domains assembling into a heart-shaped molecule, with principal ligand-binding regions located in hydrophobic cavities in subdomains IIA and IIIA that exhibit similar chemistry.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure with functional site identification, >2500 citations\",\n      \"pmids\": [\"1630489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Crystal structure of HSA complexed with five molecules of myristate at 2.5 Å resolution revealed that fatty acids bind in long hydrophobic pockets capped by polar (often basic) side chains, and that these pockets are distributed asymmetrically throughout the molecule despite its symmetrical repeating domain structure.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Nature structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution co-crystal structure defining fatty acid binding sites, >1000 citations\",\n      \"pmids\": [\"9731778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A new triclinic crystal form of HSA at 2.5 Å resolution confirmed that Cys34 is the only free sulfhydryl group not in a disulfide bond, and showed that domains II and III both contain hydrophobic, positively charged pockets capable of accommodating a wide range of compounds; three tentative fatty acid binding sites were identified at domain surfaces.\",\n      \"method\": \"X-ray crystallography (molecular replacement)\",\n      \"journal\": \"Protein engineering\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — independent high-resolution crystal structure replicating and extending prior structural findings\",\n      \"pmids\": [\"10388840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"High-resolution crystal structures of HSA complexed with the general anesthetics propofol and halothane showed that propofol binds at two discrete sites and halothane at three sites (at pharmacologically relevant concentrations), all of which are fatty acid binding loci; binding causes only minor local structural changes.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — co-crystal structures of drug–albumin complexes at high resolution, >400 citations\",\n      \"pmids\": [\"10940303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The neonatal Fc receptor FcRn was shown to bind albumin in a pH-dependent manner; FcRn-deficient mice had shortened albumin lifespan and plasma albumin concentrations less than half those of wild-type mice, demonstrating that FcRn protects albumin from degradation and prolongs its half-life.\",\n      \"method\": \"pH-dependent binding assay; FcRn knockout mouse model with pharmacokinetic measurements\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay plus genetic loss-of-function with quantitative pharmacokinetic readout, >500 citations\",\n      \"pmids\": [\"12566415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystallographic analysis of 17 HSA–drug complexes identified the precise architecture of two primary drug-binding sites (Sudlow sites I and II in subdomains IIA and IIIA), key residues determining binding specificity, and numerous secondary binding sites; fatty acid binding was shown to alter the polarity and increase the volume of drug site 1.\",\n      \"method\": \"X-ray crystallography (17 co-crystal structures)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic co-crystal structure series with multiple ligands and functional interpretation, >1300 citations\",\n      \"pmids\": [\"16169013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human plasma albumin was demonstrated to possess esterase activity toward alpha- and beta-naphthylacetate and p-nitrophenyl acetate, as shown by nondenaturing gradient gel electrophoresis with esterase activity staining; human plasma was also shown to lack carboxylesterase activity entirely.\",\n      \"method\": \"Nondenaturing gradient gel electrophoresis with esterase activity staining; enzyme kinetics\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with direct protein identification, replicated across species, >400 citations\",\n      \"pmids\": [\"16213467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Albumin's antioxidant properties were characterized, including its roles in ligand binding and free radical trapping; the single free thiol at Cys34 was identified as the principal site of free radical scavenging activity, and glycation and oxidative modifications were shown to alter these antioxidant functions.\",\n      \"method\": \"Review integrating in vitro oxidative stress assays and biochemical characterization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — synthesis of multiple experimental studies; antioxidant mechanism at Cys34 supported by multiple labs\",\n      \"pmids\": [\"18474236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Reduced/thiol-active albumin (SH-Alb) was shown to inhibit pro-fibrotic macrophage phenotype remodeling through the SIRT3–SOD2 axis: SH-Alb promoted SIRT3 expression, which deacetylated SOD2 (a key mitochondrial ROS-producing enzyme), reducing ROS accumulation; SH-Alb also reduced pro-inflammatory/pro-fibrotic cytokine release via the MAPK signaling pathway, and macrophages altered by SH-Alb inhibited hepatic stellate cell and endothelial cell activation.\",\n      \"method\": \"In vivo mouse liver fibrosis model; in vitro macrophage assays; Western blot; MAPK pathway inhibition\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo assays with defined pathway (SIRT3-SOD2/MAPK) by single lab\",\n      \"pmids\": [\"38876053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WTAP was shown to suppress ALB expression in osteosarcoma cells in an m6A-dependent manner: WTAP knockdown increased ALB mRNA and protein levels, Me-RIP and dual luciferase reporter assays confirmed WTAP targets ALB mRNA via m6A modification, and ALB knockdown reversed the anti-tumor effects of WTAP silencing on cell viability, migration, and invasion.\",\n      \"method\": \"Me-RIP; dual luciferase reporter assay; m6A quantification; siRNA knockdown; CCK-8, wound healing, and transwell invasion assays; xenograft mouse model\",\n      \"journal\": \"Environmental toxicology / Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A writer-target relationship validated by Me-RIP and reporter assay plus functional rescue, single lab\",\n      \"pmids\": [\"36988233\", \"36690262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALB overexpression in clear cell renal cell carcinoma (ccRCC) cells suppressed proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), activated endoplasmic reticulum stress (ERS) in vitro and in vivo, and was causally associated with γδT cell infiltration; mechanistically, ALB showed a negative association with SPARC, which was identified as a potential mediator of EMT downstream of ALB.\",\n      \"method\": \"ALB overexpression/knockdown in ccRCC cell lines; xenograft tumor model; Mendelian randomization (GWAS-based causal inference); functional assays (proliferation, migration, invasion); Western blot; ERS marker assessment\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, ALB–SPARC association inferred rather than mechanistically demonstrated; ERS activation shown in vitro/vivo but pathway mechanism not fully resolved\",\n      \"pmids\": [\"39862995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ALB overexpression in metastatic ccRCC cell lines suppressed proliferation, EMT, and glycolytic activity (reduced glycolytic intermediates, glucose uptake, and lactate production as measured by Seahorse metabolic flux analysis); silencing SPARC or inhibiting glycolysis reversed the malignant phenotypes induced by ALB knockdown, placing SPARC as a downstream effector through which ALB regulates EMT and glycolysis.\",\n      \"method\": \"ALB overexpression/knockdown; Seahorse glycolytic flux analysis; SPARC knockdown; transwell/migration assays; Western blot; metabolomic analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional link between ALB, SPARC, and glycolysis supported by rescue experiments but mechanistic details of ALB–SPARC interaction not biochemically defined\",\n      \"pmids\": [\"41610717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Heterozygous gain-of-function variants in the ALB gene (including p.Arg242His) cause familial dysalbuminemic hyperthyroxinemia (FDH) by producing an albumin variant with altered thyroid hormone-binding affinity, leading to elevated circulating total T4 with normal physiological thyroid function; ALB hotspot sequencing was validated as the definitive diagnostic method.\",\n      \"method\": \"Sanger sequencing of ALB gene; protein structure analysis; thyroid function testing across family members\",\n      \"journal\": \"Annals of laboratory medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genotype–phenotype linkage with family segregation and structural interpretation; replicated in multiple subsequent case reports\",\n      \"pmids\": [\"27834068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Analysis of bisalbuminemia in Korean patients identified ALB gene variants (including a novel Lys198Ile missense mutation) and showed that the mutation sites were not located within known protein-binding loci; 3D structural modeling confirmed that these variants alter albumin electrophoretic mobility without affecting binding affinity for common biochemical compounds.\",\n      \"method\": \"Serum protein electrophoresis; Sanger sequencing; 3D molecular modeling of albumin variants\",\n      \"journal\": \"The Korean journal of laboratory medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — structural modeling rather than direct biochemical binding assay; single-lab case report\",\n      \"pmids\": [\"20603593\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human serum albumin (ALB) is a three-domain, predominantly alpha-helical plasma protein whose crystal structures have precisely defined two primary drug-binding sites (Sudlow sites I and II in subdomains IIA and IIIA) and multiple fatty acid-binding pockets distributed asymmetrically across the molecule; its long plasma half-life is maintained by pH-dependent binding to FcRn, which rescues it from lysosomal degradation; it possesses intrinsic esterase activity and antioxidant activity centered on the free thiol at Cys34; its thiol redox state (SH-Alb) modulates macrophage phenotype through the SIRT3–SOD2 axis and MAPK signaling; and its expression is post-transcriptionally suppressed by the m6A writer WTAP in osteosarcoma, with gain-of-function variants in ALB causing familial dysalbuminemic hyperthyroxinemia by altering thyroid hormone-binding affinity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Human serum albumin (ALB) is the principal plasma transport protein synthesized by hepatocytes, functioning as a carrier for endogenous ligands including thyroxine; heterozygous missense variants at residue Arg242 (His or Pro) increase albumin's binding affinity for T4, causing familial dysalbuminemic hyperthyroxinemia [PMID:27834068]. ALB mRNA is post-transcriptionally regulated by WTAP-mediated m6A methylation, which modulates transcript stability and expression levels [PMID:36988233]. In its reduced-thiol form, albumin attenuates liver fibrosis by promoting SIRT3-dependent deacetylation of SOD2, thereby reducing mitochondrial ROS in macrophages [PMID:38876053], and in renal carcinoma cells ALB overexpression suppresses EMT and glycolysis through downregulation of SPARC and activation of endoplasmic reticulum stress [PMID:41610717, PMID:39862995].\",\n  \"teleology\": [\n    {\n      \"year\": 1982,\n      \"claim\": \"Establishing that ALB protein is transiently present in differentiating cells of all three germ layers during fetal development — not solely in hepatocytes — raised the question of whether albumin has developmental roles beyond plasma transport.\",\n      \"evidence\": \"Immunocytochemistry on rat fetal/neonatal tissues across developmental stages\",\n      \"pmids\": [\"6181479\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Localization study only — no functional consequence demonstrated\", \"No mechanism for ALB uptake versus local synthesis in non-hepatic tissues\", \"Not replicated in human fetal tissues\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of bisalbuminemia-causing ALB variants (Asp293Gly, Lys198Ile) and structural modeling showed that these mutations alter electrophoretic mobility without affecting ligand-binding sites, establishing that not all ALB coding variants have functional binding consequences.\",\n      \"evidence\": \"Sanger sequencing, serum protein electrophoresis, 3D structural modeling of albumin\",\n      \"pmids\": [\"20603593\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vitro binding reconstitution to directly measure ligand affinity\", \"Limited to electrophoretic and structural prediction evidence\", \"Single-laboratory observation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two distinct functional facets of the ALB locus emerged: (1) missense variants at Arg242 were shown to alter thyroxine-binding affinity causing familial dysalbuminemic hyperthyroxinemia, defining ALB as a Mendelian disease gene; (2) a lncRNA designated ALB was found to regulate autophagy in lens epithelial cells by promoting LC3BI-to-LC3BII conversion.\",\n      \"evidence\": \"Family segregation analysis with multi-platform thyroid immunoassays for FDH; siRNA knockdown with LC3BII Western blot in lens epithelial cells and lentoid bodies\",\n      \"pmids\": [\"27834068\", \"34142517\", \"29246299\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biophysical measurement of variant albumin–T4 binding affinity not reported in these studies\", \"lncRNA ALB autophagy mechanism (direct LC3 interaction vs. upstream regulation) not resolved\", \"Relationship between the lncRNA ALB and the protein-coding ALB gene not clarified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that WTAP-mediated m6A methylation targets ALB mRNA to reduce its stability revealed an epitranscriptomic layer of ALB regulation, linking ALB expression to the m6A machinery.\",\n      \"evidence\": \"Me-RIP, dual luciferase reporter, mRNA stability assays, and WTAP knockdown/rescue in osteosarcoma cells with xenograft validation\",\n      \"pmids\": [\"36988233\", \"36690262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether m6A regulation of ALB occurs in hepatocytes (the physiological source) is untested\", \"Specific m6A sites on ALB mRNA not mapped at nucleotide resolution\", \"Reader protein mediating ALB mRNA decay not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reduced-thiol albumin (SH-Alb) was shown to attenuate liver fibrosis through a defined mechanism: it upregulates SIRT3, which deacetylates mitochondrial SOD2 to reduce ROS, while also suppressing MAPK-mediated cytokine release in macrophages.\",\n      \"evidence\": \"Mouse liver fibrosis model, Western blot, SIRT3/SOD2 deacetylation assay, hepatic stellate cell and endothelial cell co-culture\",\n      \"pmids\": [\"38876053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between SH-Alb and a macrophage receptor triggering SIRT3 upregulation not identified\", \"Whether oxidized albumin has the opposite effect not tested\", \"Single-laboratory finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ALB overexpression in ccRCC cells was shown to suppress malignant phenotypes (EMT, glycolysis) through SPARC downregulation and to activate endoplasmic reticulum stress, positioning ALB as a tumor-suppressive factor in renal carcinoma.\",\n      \"evidence\": \"Seahorse metabolic flux, metabolomics, SPARC knockdown rescue, ERS pathway analysis, xenograft models in ccRCC cell lines\",\n      \"pmids\": [\"41610717\", \"39862995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ALB downregulates SPARC (direct binding, transcriptional, or indirect) not resolved\", \"Whether ERS activation is a cause or consequence of ALB-mediated tumor suppression unclear\", \"Relevance to physiological hepatocyte-secreted albumin versus ectopic overexpression not distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the cell-surface receptor(s) through which albumin activates intracellular signaling pathways (SIRT3, ERS), the structural basis for how Arg242 variants increase T4 affinity, and whether m6A-dependent regulation of ALB mRNA operates in hepatocytes to control circulating albumin levels.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biophysical study of Arg242 variant–T4 interaction\", \"Albumin receptor mediating anti-fibrotic signaling unidentified\", \"Hepatocyte-specific m6A regulation of ALB untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"WTAP\",\n      \"SPARC\",\n      \"SIRT3\",\n      \"SOD2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Insufficient on-target evidence to synthesize a narrative — discovery timeline does not match the canonical ALB protein.\",\n  \"teleology\": [],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}\n```"}