{"id":"0ad177dc-6917-59db-861a-59452e16680c","stable_key":"8c946991-97f0-55ee-8df0-00e67621962f:nad-plus-pyruvate-metformin","predicate":"restores","statement":"Pyruvate supplied an alternative electron-acceptor route for NAD+ regeneration and aspartate synthesis, reducing the antiproliferative effect of metformin in the tested cancer cells.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"a69cc58c-beb7-577f-8c23-9faa4921d168","mechanism_event_label":"Available nutrients can change the effect of an inhibitor on the same pathway.","subject":{"id":"91e6d4f5-fba1-542d-b68a-57cc28e1e425","slug":"pyruvate","display_name":"Pyruvate","entity_type_key":"small_molecule"},"object":{"id":"2ae86193-e2fc-51fd-b857-257ec2868aca","slug":"human-cancer-cell-nad-regeneration","display_name":"NAD regeneration in metformin-treated cancer cells","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"a69cc58c-beb7-577f-8c23-9faa4921d168","stable_key":"8c946991-97f0-55ee-8df0-00e67621962f:nad-plus-pyruvate-metformin-event","event_type":"observed_relationship","label":"Available nutrients can change the effect of an inhibitor on the same pathway.","description":"Pyruvate supplied an alternative electron-acceptor route for NAD+ regeneration and aspartate synthesis, reducing the antiproliferative effect of metformin in the tested cancer cells.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"91e6d4f5-fba1-542d-b68a-57cc28e1e425","slug":"pyruvate","display_name":"Pyruvate","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"2ae86193-e2fc-51fd-b857-257ec2868aca","slug":"human-cancer-cell-nad-regeneration","display_name":"NAD regeneration in metformin-treated cancer cells","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"283ed24b-06a1-50aa-9281-df3bac6ce37e","slug":"nad-plus","display_name":"NAD+","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"9fbf2e03-16a9-5ca7-965c-0bfc07ca24da","slug":"nadh","display_name":"NADH","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"0a0923d3-72b7-5d6a-bf3a-5a7a3071a09b","slug":"l-aspartate","display_name":"L-Aspartate","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"519971b1-5aef-5ad7-8022-840144855cd0","slug":"metformin","display_name":"Metformin","entity_type_key":"drug"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_access","value_text":"Primary full text","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Experimental concentrations and culture composition matter; not a medication adjustment or claim that metformin has one mechanism in all tissues.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"NAD+ collection; molecular form, preparation, species, exposure and manipulation remain explicit.","comparator":null,"unit":null,"notes":"","entity":{"slug":"nad-plus","display_name":"NAD+","entity_type_key":"small_molecule"}},{"dimension":"plain_language","value_text":"Available nutrients can change the effect of an inhibitor on the same pathway.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Environment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"ec878894-178d-5cd5-badd-093def2b8384","evidence_kind":"source_excerpt","locator":"Lines 220-226","start_line":220,"end_line":226,"excerpt":"## nad-plus-pyruvate-metformin\nAvailable nutrients can change the effect of an inhibitor on the same pathway.\nPyruvate supplied an alternative electron-acceptor route for NAD+ regeneration and aspartate synthesis, reducing the antiproliferative effect of metformin in the tested cancer cells.\nModel: Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation.\nLimitations: Experimental concentrations and culture composition matter; not a medication adjustment or claim that metformin has one mechanism in all tissues.\nEvidence access: Primary full text\nEnvironment Dictates Dependence on Mitochondrial Complex I for NAD+ and Aspartate Production and Determines Cancer Cell Sensitivity to Metformin. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27746050/ · DOI 10.1016/j.cmet.2016.09.006","model_system":"Cancer-cell culture, complex-I-dependent respiration and nutrient manipulation.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"Original curation paraphrase; evidence access and experimental limitations specified.","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"f59aa302-d463-5462-876f-e21e64861eac","stable_key":"import-8c946991-97f0-55ee-8df0-00e67621962f","title":"NAD+: compartmental supply, consumption and cross-nutrient mechanisms (2026-09-19)","document_type":"imported_text","citation_label":"AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text.","file_path":"","sha256":"9f5324d0d652c80ad630b3100e28ce34cd2ce260ea2e1324332a4262ce72ae09","revision_id":"0e07909c-e8bc-5950-bafc-61371d9d6412","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}