{"gene":"CS","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2023,"finding":"HBV stimulation causes hyperacetylation of citrate synthase (CS) in macrophages, which inhibits CS enzymatic activity, impairs the TCA cycle, and drives M2-like macrophage polarization. HBV downregulates SIRT3 (a mitochondrial deacetylase) via the TLR2–NF-κB–PGC-1α axis, resulting in CS hyperacetylation; restoration of TCA cycle activity with dichloroacetate reversed M2 polarization and reduced serum HBV DNA in vivo.","method":"Immunoprecipitation (to detect acetylation of CS), western blot, metabolomics, flow cytometry, in vivo chronic HBV mouse model with dichloroacetate treatment","journal":"Hepatology communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP for acetylation, enzymatic activity assays, and in vivo rescue experiment, but single lab with no independent replication reported","pmids":["37820280"],"is_preprint":false},{"year":2024,"finding":"miR-122-5p overexpression suppresses citrate synthase (CS) expression in nasopharyngeal carcinoma (NPC) cells, and this suppression promotes erastin-induced ferroptosis, as measured by increased lipid peroxidation markers (MDA, Fe2+, ROS), decreased glutathione, and mitochondrial morphology changes; the effect was confirmed in a subcutaneous mouse NPC model.","method":"miR-122-5p overexpression/silencing, CS knockdown/overexpression, ferroptosis assays (MDA, Fe2+, GSH, ROS, mitochondrial morphology), cell proliferation/migration assays, in vivo mouse xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined phenotypic readout (ferroptosis) and in vivo validation, single lab, multiple orthogonal methods","pmids":["38693171"],"is_preprint":false}],"current_model":"Citrate synthase (CS) catalyzes the first step of the TCA cycle; its enzymatic activity is negatively regulated by SIRT3-dependent deacetylation (hyperacetylation inhibits activity), and its expression level modulates ferroptosis sensitivity in cancer cells by influencing mitochondrial metabolism and lipid peroxidation."},"narrative":{"mechanistic_narrative":"Citrate synthase (CS) is a mitochondrial enzyme whose activity gates TCA cycle flux and thereby couples mitochondrial metabolism to cell-state decisions in immune and cancer cells [PMID:37820280, PMID:38693171]. In macrophages, HBV stimulation downregulates the mitochondrial deacetylase SIRT3 through a TLR2–NF-κB–PGC-1α axis, leading to hyperacetylation of CS that inhibits its enzymatic activity, impairs the TCA cycle, and drives M2-like polarization; restoring TCA flux with dichloroacetate reverses this polarization and lowers viral load in vivo [PMID:37820280]. In nasopharyngeal carcinoma cells, CS expression is suppressed by miR-122-5p, and loss of CS sensitizes cells to erastin-induced ferroptosis, marked by increased lipid peroxidation, iron accumulation, ROS, and glutathione depletion [PMID:38693171]. Beyond these acetylation-dependent and expression-level controls of CS activity, no further mechanistic detail on CS has been characterized in the available corpus.","teleology":[{"year":2023,"claim":"Established that CS activity is controlled post-translationally by acetylation and that this control links viral signaling to macrophage metabolic reprogramming, answering how HBV reshapes immune cell fate through the TCA cycle.","evidence":"Immunoprecipitation of acetylated CS, enzymatic activity assays, metabolomics, and an in vivo chronic HBV mouse model with dichloroacetate rescue","pmids":["37820280"],"confidence":"Medium","gaps":["Specific acetylated lysine residues on CS not mapped","Direct SIRT3–CS deacetylation not reconstituted biochemically","Single lab, no independent replication"]},{"year":2024,"claim":"Established that CS expression level tunes ferroptosis sensitivity, answering how a metabolic enzyme influences lipid peroxidation-driven cell death in cancer.","evidence":"miR-122-5p gain/loss-of-function, CS knockdown/overexpression with ferroptosis readouts (MDA, Fe2+, GSH, ROS, mitochondrial morphology), and in vivo NPC xenograft","pmids":["38693171"],"confidence":"Medium","gaps":["Mechanism linking CS metabolic output to lipid peroxidation not defined","Whether the effect depends on CS catalytic activity vs. protein level untested","Single lab and single tumor context"]},{"year":null,"claim":"Whether acetylation-dependent regulation of CS and CS-dependent control of ferroptosis represent a unified metabolic mechanism across cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of regulated CS","Acetylation sites unmapped","Connection between TCA flux and lipid peroxidation pathway not mechanistically traced"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75390","full_name":"Citrate synthase, mitochondrial","aliases":["Citrate (Si)-synthase"],"length_aa":466,"mass_kda":51.7,"function":"Key enzyme of the Krebs tricarboxylic acid cycle which catalyzes the synthesis of citrate from acetyl coenzyme A and oxaloacetate","subcellular_location":"Mitochondrion matrix","url":"https://www.uniprot.org/uniprotkb/O75390/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CS","classification":"Common Essential","n_dependent_lines":513,"n_total_lines":1208,"dependency_fraction":0.4246688741721854},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ASS1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLIP1","stoichiometry":0.2},{"gene":"HEATR3","stoichiometry":0.2},{"gene":"HSP90B1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CS","total_profiled":1310},"omim":[{"mim_id":"621535","title":"SPINOCEREBELLAR ATAXIA 52; SCA52","url":"https://www.omim.org/entry/621535"},{"mim_id":"621530","title":"CWC25, SPLICEOSOME-ASSOCIATED PROTEIN; CWC25","url":"https://www.omim.org/entry/621530"},{"mim_id":"621518","title":"SYNAPTOTAGMIN 17; SYT17","url":"https://www.omim.org/entry/621518"},{"mim_id":"621379","title":"NEUROCARDIORENAL MALFORMATION SYNDROME; NCRMS","url":"https://www.omim.org/entry/621379"},{"mim_id":"621258","title":"FANCONI ANEMIA, COMPLEMENTATION GROUP X; FANCX","url":"https://www.omim.org/entry/621258"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":515.2},{"tissue":"tongue","ntpm":561.0}],"url":"https://www.proteinatlas.org/search/CS"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"O75390","domains":[{"cath_id":"1.10.580.10","chopping":"138-301_416-443","consensus_level":"high","plddt":98.5176,"start":138,"end":443},{"cath_id":"1.10.230.10","chopping":"304-413","consensus_level":"medium","plddt":96.5804,"start":304,"end":413}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75390","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75390-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75390-F1-predicted_aligned_error_v6.png","plddt_mean":94.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CS","jax_strain_url":"https://www.jax.org/strain/search?query=CS"},"sequence":{"accession":"O75390","fasta_url":"https://rest.uniprot.org/uniprotkb/O75390.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75390/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75390"}},"corpus_meta":[{"pmid":"11258478","id":"PMC_11258478","title":"The atypical protein kinase Cs. 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CS-67 capable of accumulating heavy metal ions.","date":"2022","source":"Ecotoxicology and environmental safety","url":"https://pubmed.ncbi.nlm.nih.gov/35405529","citation_count":21,"is_preprint":false},{"pmid":"2094581","id":"PMC_2094581","title":"Localization of CS and non-CS antigens in the sporogonic stages of Plasmodium yoelii.","date":"1990","source":"Bulletin of the World Health Organization","url":"https://pubmed.ncbi.nlm.nih.gov/2094581","citation_count":20,"is_preprint":false},{"pmid":"31477108","id":"PMC_31477108","title":"Lyn regulates epithelial-mesenchymal transition in CS-exposed model through Smad2/3 signaling.","date":"2019","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/31477108","citation_count":20,"is_preprint":false},{"pmid":"36414263","id":"PMC_36414263","title":"Frenkel Excitons in Vacancy-Ordered Titanium Halide Perovskites (Cs2TiX6).","date":"2022","source":"The journal of physical chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/36414263","citation_count":20,"is_preprint":false},{"pmid":"28987564","id":"PMC_28987564","title":"Roles of CSGalNAcT1, a key enzyme in regulation of CS synthesis, in neuronal regeneration and plasticity.","date":"2017","source":"Neurochemistry international","url":"https://pubmed.ncbi.nlm.nih.gov/28987564","citation_count":19,"is_preprint":false},{"pmid":"32023805","id":"PMC_32023805","title":"Impact of Prevalence Ratios of Chondroitin Sulfate (CS)- 4 and -6 Isomers Derived from Marine Sources in Cell Proliferation and Chondrogenic Differentiation Processes.","date":"2020","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/32023805","citation_count":19,"is_preprint":false},{"pmid":"2692950","id":"PMC_2692950","title":"Cefmetazole (CS-1170), a \"new\" cephamycin with a decade of clinical experience.","date":"1989","source":"Diagnostic microbiology and infectious disease","url":"https://pubmed.ncbi.nlm.nih.gov/2692950","citation_count":19,"is_preprint":false},{"pmid":"37272677","id":"PMC_37272677","title":"Perovskite-Derived Bismuth with I- and Cs+ Dual Modification for High-Efficiency CO2 -to-Formate Electrosynthesis and Al-CO2 Batteries.","date":"2023","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/37272677","citation_count":18,"is_preprint":false},{"pmid":"33519271","id":"PMC_33519271","title":"Immune system response during viral Infections: Immunomodulators, cytokine storm (CS) and Immunotherapeutics in COVID-19.","date":"2021","source":"Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society","url":"https://pubmed.ncbi.nlm.nih.gov/33519271","citation_count":18,"is_preprint":false},{"pmid":"32605115","id":"PMC_32605115","title":"Characterization, Biocompatibility, and Optimization of Electrospun SF/PCL/CS Composite Nanofibers.","date":"2020","source":"Polymers","url":"https://pubmed.ncbi.nlm.nih.gov/32605115","citation_count":17,"is_preprint":false},{"pmid":"37820280","id":"PMC_37820280","title":"HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation.","date":"2023","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/37820280","citation_count":17,"is_preprint":false},{"pmid":"34194668","id":"PMC_34194668","title":"Zeta-carbonic anhydrases show CS2 hydrolase activity: A new metabolic carbon acquisition pathway in diatoms?","date":"2021","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/34194668","citation_count":17,"is_preprint":false},{"pmid":"28049392","id":"PMC_28049392","title":"Chondroitin Sulfate (CS) Lyases: Structure, Function and Application in Therapeutics.","date":"2018","source":"Current protein & peptide science","url":"https://pubmed.ncbi.nlm.nih.gov/28049392","citation_count":16,"is_preprint":false},{"pmid":"37640689","id":"PMC_37640689","title":"An S=1 Iron(IV) Intermediate Revealed in a Non-Heme Iron Enzyme-Catalyzed Oxidative C-S Bond Formation.","date":"2023","source":"Angewandte Chemie (International ed. in English)","url":"https://pubmed.ncbi.nlm.nih.gov/37640689","citation_count":15,"is_preprint":false},{"pmid":"24130907","id":"PMC_24130907","title":"TLR and NKG2D signaling pathways mediate CS-induced pulmonary pathologies.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24130907","citation_count":15,"is_preprint":false},{"pmid":"34510734","id":"PMC_34510734","title":"Bacterial flavoprotein monooxygenase YxeK salvages toxic S-(2-succino)-adducts via oxygenolytic C-S bond cleavage.","date":"2021","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/34510734","citation_count":14,"is_preprint":false},{"pmid":"19697154","id":"PMC_19697154","title":"BCR/ABL downregulates DNA-PK(CS)-dependent and upregulates backup non-homologous end joining in leukemic cells.","date":"2009","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19697154","citation_count":13,"is_preprint":false},{"pmid":"8979294","id":"PMC_8979294","title":"Protein kinase Cs and tyrosine kinases in permissive action of prostacyclin on cerebrovascular regulation in newborn pigs.","date":"1997","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/8979294","citation_count":13,"is_preprint":false},{"pmid":"35537200","id":"PMC_35537200","title":"Monitoring Noble Gases (Xe and Kr) and Aerosols (Cs and Rb) in a Molten Salt Reactor Surrogate Off-Gas Stream Using Laser-Induced Breakdown Spectroscopy (LIBS).","date":"2022","source":"Applied spectroscopy","url":"https://pubmed.ncbi.nlm.nih.gov/35537200","citation_count":13,"is_preprint":false},{"pmid":"10202812","id":"PMC_10202812","title":"Expression characteristics of CS-ACS1, CS-ACS2 and CS-ACS3, three members of the 1-aminocyclopropane-1-carboxylate synthase gene family in cucumber (Cucumis sativus L.) fruit under carbon dioxide stress.","date":"1999","source":"Plant & cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10202812","citation_count":13,"is_preprint":false},{"pmid":"25944184","id":"PMC_25944184","title":"CS-SCORE: Rapid identification and removal of human genome contaminants from metagenomic datasets.","date":"2015","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/25944184","citation_count":13,"is_preprint":false},{"pmid":"28522840","id":"PMC_28522840","title":"Kup-mediated Cs+ uptake and Kdp-driven K+ uptake coordinate to promote cell growth during excess Cs+ conditions in Escherichia coli.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28522840","citation_count":13,"is_preprint":false},{"pmid":"3086454","id":"PMC_3086454","title":"Immunogenicity of the repetitive and nonrepetitive peptide regions of the divergent CS protein of Plasmodium knowlesi.","date":"1986","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/3086454","citation_count":13,"is_preprint":false},{"pmid":"18065172","id":"PMC_18065172","title":"Improved transfection efficiency of CS/DNA complex by co-transfected chitosanase gene.","date":"2007","source":"International journal of pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/18065172","citation_count":12,"is_preprint":false},{"pmid":"11809805","id":"PMC_11809805","title":"Atypical protein kinase Cs are the Ras effectors that mediate repression of myogenic satellite cell differentiation.","date":"2002","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11809805","citation_count":12,"is_preprint":false},{"pmid":"32582089","id":"PMC_32582089","title":"Comparison of Meconium Microbiome in Dizygotic and Monozygotic Twins Born by Caesarean Section (CS).","date":"2020","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32582089","citation_count":12,"is_preprint":false},{"pmid":"38910038","id":"PMC_38910038","title":"CS proteins and ubiquitination: orchestrating DNA repair with transcription and cell division.","date":"2024","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38910038","citation_count":11,"is_preprint":false},{"pmid":"38693171","id":"PMC_38693171","title":"MiR-122-5p regulates erastin-induced ferroptosis via CS in nasopharyngeal carcinoma.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38693171","citation_count":11,"is_preprint":false},{"pmid":"31672602","id":"PMC_31672602","title":"The promotion of bone regeneration through CS/GP-CTH/antagomir-133a/b sustained release system.","date":"2019","source":"Nanomedicine : nanotechnology, biology, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31672602","citation_count":11,"is_preprint":false},{"pmid":"36430547","id":"PMC_36430547","title":"A, B, C's of Trk Receptors and Their Ligands in Ocular Repair.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36430547","citation_count":11,"is_preprint":false},{"pmid":"37229602","id":"PMC_37229602","title":"Alkylcysteine Sulfoxide C-S Monooxygenase Uses a Flavin-Dependent Pummerer Rearrangement.","date":"2023","source":"Journal of the American Chemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/37229602","citation_count":11,"is_preprint":false},{"pmid":"35428946","id":"PMC_35428946","title":"Inflammasome involvement in CS-induced damage in HaCaT keratinocytes.","date":"2022","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/35428946","citation_count":11,"is_preprint":false},{"pmid":"2504130","id":"PMC_2504130","title":"Mutagenicity and cytotoxicity of 2-chlorobenzylidene malonitrile (CS) and metabolites in V79 Chinese hamster cells.","date":"1989","source":"Archives of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/2504130","citation_count":11,"is_preprint":false},{"pmid":"36365465","id":"PMC_36365465","title":"PVP/CS/Phyllanthus emblica Nanofiber Membranes for Dry Facial Masks: Manufacturing Process and Evaluations.","date":"2022","source":"Polymers","url":"https://pubmed.ncbi.nlm.nih.gov/36365465","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48059,"output_tokens":1016,"usd":0.079709,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7076,"output_tokens":1304,"usd":0.03399,"stage2_stop_reason":"end_turn"},"total_usd":0.113699,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human gene CS (Citrate Synthase). Let me scan through the abstracts carefully.\n\nPaper [77] (PMID:37820280) is directly relevant: it studies citrate synthase (CS) in macrophages, showing HBV induces hyperacetylation of CS, inhibiting its enzymatic activity, impairing the TCA cycle, leading to M2-like macrophage polarization. The deacetylase SIRT3 is implicated.\n\nPaper [94] (PMID:38693171) is relevant: it studies citrate synthase (CS) in NPC cells, showing miR-122-5p overexpression inhibits CS, promoting erastin-induced ferroptosis.\n\nMost other papers use \"CS\" as abbreviations for completely different things (circumsporozoite protein, cigarette smoke, Cockayne syndrome, chitosan, protein kinase Cs, etc.) and are not about the human Citrate Synthase gene.\n\nLet me verify paper [77] more carefully: \"Citrate synthase/pyruvate dehydrogenase complex hyperacetylation in macrophages after HBV stimulation inhibited their enzymatic activities\" — yes, this is about citrate synthase (CS gene product).\n\nPaper [94]: \"miR-122-5p overexpression inhibited CS, thereby promoting erastin-induced ferroptosis\" — CS here refers to citrate synthase based on context.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2023,\n      \"finding\": \"HBV stimulation causes hyperacetylation of citrate synthase (CS) in macrophages, which inhibits CS enzymatic activity, impairs the TCA cycle, and drives M2-like macrophage polarization. HBV downregulates SIRT3 (a mitochondrial deacetylase) via the TLR2–NF-κB–PGC-1α axis, resulting in CS hyperacetylation; restoration of TCA cycle activity with dichloroacetate reversed M2 polarization and reduced serum HBV DNA in vivo.\",\n      \"method\": \"Immunoprecipitation (to detect acetylation of CS), western blot, metabolomics, flow cytometry, in vivo chronic HBV mouse model with dichloroacetate treatment\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP for acetylation, enzymatic activity assays, and in vivo rescue experiment, but single lab with no independent replication reported\",\n      \"pmids\": [\"37820280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-122-5p overexpression suppresses citrate synthase (CS) expression in nasopharyngeal carcinoma (NPC) cells, and this suppression promotes erastin-induced ferroptosis, as measured by increased lipid peroxidation markers (MDA, Fe2+, ROS), decreased glutathione, and mitochondrial morphology changes; the effect was confirmed in a subcutaneous mouse NPC model.\",\n      \"method\": \"miR-122-5p overexpression/silencing, CS knockdown/overexpression, ferroptosis assays (MDA, Fe2+, GSH, ROS, mitochondrial morphology), cell proliferation/migration assays, in vivo mouse xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined phenotypic readout (ferroptosis) and in vivo validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38693171\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Citrate synthase (CS) catalyzes the first step of the TCA cycle; its enzymatic activity is negatively regulated by SIRT3-dependent deacetylation (hyperacetylation inhibits activity), and its expression level modulates ferroptosis sensitivity in cancer cells by influencing mitochondrial metabolism and lipid peroxidation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Citrate synthase (CS) is a mitochondrial enzyme whose activity gates TCA cycle flux and thereby couples mitochondrial metabolism to cell-state decisions in immune and cancer cells [#0, #1]. In macrophages, HBV stimulation downregulates the mitochondrial deacetylase SIRT3 through a TLR2\\u2013NF-\\u03baB\\u2013PGC-1\\u03b1 axis, leading to hyperacetylation of CS that inhibits its enzymatic activity, impairs the TCA cycle, and drives M2-like polarization; restoring TCA flux with dichloroacetate reverses this polarization and lowers viral load in vivo [#0]. In nasopharyngeal carcinoma cells, CS expression is suppressed by miR-122-5p, and loss of CS sensitizes cells to erastin-induced ferroptosis, marked by increased lipid peroxidation, iron accumulation, ROS, and glutathione depletion [#1]. Beyond these acetylation-dependent and expression-level controls of CS activity, no further mechanistic detail on CS has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that CS activity is controlled post-translationally by acetylation and that this control links viral signaling to macrophage metabolic reprogramming, answering how HBV reshapes immune cell fate through the TCA cycle.\",\n      \"evidence\": \"Immunoprecipitation of acetylated CS, enzymatic activity assays, metabolomics, and an in vivo chronic HBV mouse model with dichloroacetate rescue\",\n      \"pmids\": [\"37820280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific acetylated lysine residues on CS not mapped\", \"Direct SIRT3\\u2013CS deacetylation not reconstituted biochemically\", \"Single lab, no independent replication\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established that CS expression level tunes ferroptosis sensitivity, answering how a metabolic enzyme influences lipid peroxidation-driven cell death in cancer.\",\n      \"evidence\": \"miR-122-5p gain/loss-of-function, CS knockdown/overexpression with ferroptosis readouts (MDA, Fe2+, GSH, ROS, mitochondrial morphology), and in vivo NPC xenograft\",\n      \"pmids\": [\"38693171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking CS metabolic output to lipid peroxidation not defined\", \"Whether the effect depends on CS catalytic activity vs. protein level untested\", \"Single lab and single tumor context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether acetylation-dependent regulation of CS and CS-dependent control of ferroptosis represent a unified metabolic mechanism across cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of regulated CS\", \"Acetylation sites unmapped\", \"Connection between TCA flux and lipid peroxidation pathway not mechanistically traced\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":3,"faith_total":3,"faith_pct":100.0}}