{"id":"71bdb2e8-6d72-59b5-9c52-262839460bde","stable_key":"c9aa15a1-8ba2-5913-b2dd-372af304bf87:fast-hdac-positive","predicate":"reported_to_inhibit","statement":"The study reported direct class-I HDAC inhibition by D-beta-hydroxybutyrate, alongside increased histone acetylation in mouse tissues.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"492bac74-5624-5e01-b73f-40b4cea194a7","mechanism_event_label":"One study proposed a direct route from ketones to gene regulation.","subject":{"id":"59496369-eea6-5302-a0a3-2dcfa8f2b71a","slug":"d-beta-hydroxybutyrate","display_name":"D-(R)-beta-hydroxybutyrate","entity_type_key":"small_molecule"},"object":{"id":"c5300ff9-49fe-522c-aba5-d92ec77f7aaf","slug":"class-i-hdac-activity","display_name":"Class I histone deacetylase activity","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"492bac74-5624-5e01-b73f-40b4cea194a7","stable_key":"c9aa15a1-8ba2-5913-b2dd-372af304bf87:fast-hdac-positive-event","event_type":"observed_relationship","label":"One study proposed a direct route from ketones to gene regulation.","description":"The study reported direct class-I HDAC inhibition by D-beta-hydroxybutyrate, alongside increased histone acetylation in mouse tissues.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"59496369-eea6-5302-a0a3-2dcfa8f2b71a","slug":"d-beta-hydroxybutyrate","display_name":"D-(R)-beta-hydroxybutyrate","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"c5300ff9-49fe-522c-aba5-d92ec77f7aaf","slug":"class-i-hdac-activity","display_name":"Class I histone deacetylase activity","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"evidence_access","value_text":"Primary abstract","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Biochemical/cellular experiments; mouse fasting, calorie restriction or exogenous BHB.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Later direct testing challenged HDAC inhibition; see the linked research disagreement.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Fasting physiological-state collection; human protocols, cellular deprivation and refeeding are distinguished.","comparator":null,"unit":null,"notes":"","entity":{"slug":"fasting","display_name":"Fasting / abstention from energy intake","entity_type_key":"cellular_process"}},{"dimension":"plain_language","value_text":"One study proposed a direct route from ketones to gene regulation.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23223453/ · DOI 10.1126/science.1227166","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"46d8b760-6ede-51be-b740-f8bb07f9d894","evidence_kind":"source_excerpt","locator":"Lines 392-398","start_line":392,"end_line":398,"excerpt":"## fast-hdac-positive\nOne study proposed a direct route from ketones to gene regulation.\nThe study reported direct class-I HDAC inhibition by D-beta-hydroxybutyrate, alongside increased histone acetylation in mouse tissues.\nModel: Biochemical/cellular experiments; mouse fasting, calorie restriction or exogenous BHB.\nLimitations: Later direct testing challenged HDAC inhibition; see the linked research disagreement.\nEvidence access: Primary abstract\nSuppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23223453/ · DOI 10.1126/science.1227166","model_system":"Biochemical/cellular experiments; mouse fasting, calorie restriction or exogenous BHB.","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":"921d1eb5-2c88-52b9-9898-60b2b5bf6029","stable_key":"import-c9aa15a1-8ba2-5913-b2dd-372af304bf87","title":"Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18)","document_type":"imported_text","citation_label":"AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text.","file_path":"","sha256":"991b7fd94be84c0f1e622e0672eda03d600b388dfd7825e219aa1678d1c7983a","revision_id":"ce85d3f4-4eaf-5aee-bddb-0f0ce7fe2211","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"a48ef90a-582e-5576-8b51-f1f37c6d9087","title":"Does beta-hydroxybutyrate directly inhibit HDACs?","kind":"contradiction","status":"open","why":"The 2013 primary study reports direct class-I HDAC inhibition by D-beta-hydroxybutyrate. The 2019 primary study explicitly challenges this interpretation after failing to detect inhibition in its HDAC assay or histone hyperacetylation in several cell models. This is a published mechanistic disagreement, not a correction to an earlier ledger draft.","resolution":"Unresolved. Keep both reports and assay conditions. Enzyme preparation, substrate/readout, cell metabolism and exposure could contribute, but none is established here as the explanation. Histone beta-hydroxybutyrylation is a distinct modification and does not itself prove HDAC inhibition. Do not present direct HDAC inhibition as a settled universal fasting mechanism.","created_at":"2026-09-19 02:51:14","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/a48ef90a-582e-5576-8b51-f1f37c6d9087","sides":[{"conflict_id":"a48ef90a-582e-5576-8b51-f1f37c6d9087","ordinal":0,"label":"2013: direct inhibition reported","revision_id":"ce85d3f4-4eaf-5aee-bddb-0f0ce7fe2211","start_line":392,"end_line":398,"quote":"## fast-hdac-positive\nOne study proposed a direct route from ketones to gene regulation.\nThe study reported direct class-I HDAC inhibition by D-beta-hydroxybutyrate, alongside increased histone acetylation in mouse tissues.\nModel: Biochemical/cellular experiments; mouse fasting, calorie restriction or exogenous BHB.\nLimitations: Later direct testing challenged HDAC inhibition; see the linked research disagreement.\nEvidence access: Primary abstract\nSuppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23223453/ · DOI 10.1126/science.1227166","source_key":"import-c9aa15a1-8ba2-5913-b2dd-372af304bf87","source_title":"Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18)","claim_ids":["71bdb2e8-6d72-59b5-9c52-262839460bde"]},{"conflict_id":"a48ef90a-582e-5576-8b51-f1f37c6d9087","ordinal":1,"label":"2019: inhibition not detected","revision_id":"ce85d3f4-4eaf-5aee-bddb-0f0ce7fe2211","start_line":400,"end_line":406,"quote":"## fast-hdac-negative\nAnother study did not reproduce the proposed direct effect.\nThe later study detected no HDAC inhibition with 10 mM sodium R-BHB in its nuclear-extract assay; multiple cell models lacked histone hyperacetylation up to 40 mM.\nModel: Nuclear-extract assay and HEK293, HMEC-1, rat and human myotube experiments.\nLimitations: Different preparations/readouts may matter; the discrepancy is unresolved. Concentrations are experimental, not target blood levels.\nEvidence access: Primary abstract and indexed full-text Figure 2/Discussion, PMC6346118\nProminent action of butyrate over β-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule. · 2019 · https://pubmed.ncbi.nlm.nih.gov/30679586/ · DOI 10.1038/s41598-018-36941-9","source_key":"import-c9aa15a1-8ba2-5913-b2dd-372af304bf87","source_title":"Fasting: fuel switching, nutrient sensing, ketone signaling, nutrient dependencies and refeeding (2026-09-18)","claim_ids":["6b597db3-c217-5f14-9369-f24f0df0cece"]}]}],"corrections":[],"research":null}