{"id":"ea16fae7-c4b2-57c9-830e-6eb61c969068","stable_key":"3b5aff9b-4086-5574-bfb4-3ea49ba520d7:coq10-dhodh-offtarget","predicate":"high_concentrations_inhibit","statement":"The 2023 study attributed strong ferroptosis sensitization by high concentrations of DHODH inhibitors to concurrent FSP1 inhibition.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"7e42f05d-0952-573d-8a05-ceeec389cfb1","mechanism_event_label":"A drug can affect a second enzyme, changing the explanation of its result.","subject":{"id":"4ce6fc29-6994-5a1c-9220-783b30fef44e","slug":"brequinar","display_name":"Brequinar","entity_type_key":"small_molecule"},"object":{"id":"6c60c705-b3dc-548d-a2ad-e9f75249a642","slug":"aifm2","display_name":"FSP1 / AIFM2","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"7e42f05d-0952-573d-8a05-ceeec389cfb1","stable_key":"3b5aff9b-4086-5574-bfb4-3ea49ba520d7:coq10-dhodh-offtarget-event","event_type":"biochemical_relationship","label":"A drug can affect a second enzyme, changing the explanation of its result.","description":"The 2023 study attributed strong ferroptosis sensitization by high concentrations of DHODH inhibitors to concurrent FSP1 inhibition.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"34f8e936-32ed-55ed-b0a6-8b26330abea5","slug":"dhodh","display_name":"Human dihydroorotate dehydrogenase / DHODH","entity_type_key":"protein"},"role":"intended_target","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"4ce6fc29-6994-5a1c-9220-783b30fef44e","slug":"brequinar","display_name":"Brequinar","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"6c60c705-b3dc-548d-a2ad-e9f75249a642","slug":"aifm2","display_name":"FSP1 / AIFM2","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/coq10-research/37407687.publisher-preview.txt\", \"locator\": \"Primary public publisher preview, reference superscripts removed; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"dd04682c5ac5215eff4a195cf2fcff7c5f6cf59eb659cc5710e6a2ecd09b0529\", \"start_char\": 0, \"end_char\": 477, \"text_sha256\": \"dd04682c5ac5215eff4a195cf2fcff7c5f6cf59eb659cc5710e6a2ecd09b0529\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Primary experimental Matters Arising; public publisher preview","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"DHODH inhibitors at different concentrations","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Public preview only; exact dose-response tables not extracted. Do not deny all DHODH effects or invent a universal concentration cutoff.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"coq10","display_name":"Coenzyme Q10 / CoQ10 redox system","entity_type_key":"chemical_species"}},{"dimension":"organism","value_text":"Cancer-cell inhibitor and genetic comparisons","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"A drug can affect a second enzyme, changing the explanation of its result.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[coq10-p37407687] DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. (2023). https://pubmed.ncbi.nlm.nih.gov/37407687/ DOI: 10.1038/s41586-023-06269-0","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"DHODH versus FSP1 attribution","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"76b2a492-4ebd-5f0d-9d9d-d4ae17153294","evidence_kind":"source_excerpt","locator":"Lines 840-851","start_line":840,"end_line":851,"excerpt":"### coq10-dhodh-offtarget\nThe 2023 study attributed strong ferroptosis sensitization by high concentrations of DHODH inhibitors to concurrent FSP1 inhibition.\nCondition category: normal\nnutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: A drug can affect a second enzyme, changing the explanation of its result.\norganism: Cancer-cell inhibitor and genetic comparisons\ntissue_or_cell_type: DHODH versus FSP1 attribution\nexperimental_model: Primary experimental Matters Arising; public publisher preview\nlimitations: Public preview only; exact dose-response tables not extracted. Do not deny all DHODH effects or invent a universal concentration cutoff.\nexposure: DHODH inhibitors at different concentrations\nevidence_span: {\"source_cache\": \"artifacts/coq10-research/37407687.publisher-preview.txt\", \"locator\": \"Primary public publisher preview, reference superscripts removed; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"dd04682c5ac5215eff4a195cf2fcff7c5f6cf59eb659cc5710e6a2ecd09b0529\", \"start_char\": 0, \"end_char\": 477, \"text_sha256\": \"dd04682c5ac5215eff4a195cf2fcff7c5f6cf59eb659cc5710e6a2ecd09b0529\"}\n[coq10-p37407687] DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. (2023). https://pubmed.ncbi.nlm.nih.gov/37407687/ DOI: 10.1038/s41586-023-06269-0","model_system":"Primary experimental Matters Arising; public publisher preview","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [coq10-p37407687] DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. (2023). https://pubmed.ncbi.nlm.nih.gov/37407687/ DOI: 10.1038/s41586-023-06269-0","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"fc6c2f3b-14a3-59de-848e-ca1c02fee1df","stable_key":"import-3b5aff9b-4086-5574-bfb4-3ea49ba520d7","title":"Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"053f9a6f6c17321fa9fd271486d7f20a86a49b237424108de7dc8663372e73bf","revision_id":"028900ce-8ca4-5d13-8c86-6e327c071e64","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"c96a0617-fd29-5a15-a075-d8b1f62f3b1e","title":"DHODH ferroptosis protection: mitochondrial pathway versus inhibitor off-target effects","kind":"contradiction","status":"open","why":"The 2021 study assigned substantial mitochondrial defense to DHODH. The 2023 experimental challenge argued that genetic effects were small and context-dependent and that strong inhibitor sensitization involved FSP1 inhibition. The original authors replied with counterarguments. This is a published mechanistic dispute, not an editorial correction.","resolution":"Retain the DHODH biochemical route, but do not equate inhibitor-induced ferroptosis with selective DHODH causation. Compare genetic deletion/rescue, drug concentration, direct FSP1 inhibition, GPX4 localization and cell context. The contribution of each mechanism remains unsettled.","created_at":"2026-09-17 21:53:19","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/c96a0617-fd29-5a15-a075-d8b1f62f3b1e","sides":[{"conflict_id":"c96a0617-fd29-5a15-a075-d8b1f62f3b1e","ordinal":0,"label":"2021: mitochondrial DHODH defense","revision_id":"028900ce-8ca4-5d13-8c86-6e327c071e64","start_line":827,"end_line":838,"quote":"### coq10-dhodh-loss\nDHODH inactivation increased mitochondrial lipid peroxidation and ferroptosis in the reported GPX4-dependent experimental contexts.\nCondition category: machinery_impairment\nnutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: The effect depended on which other defense route remained available.\norganism: Human cancer-cell and tumor models\ntissue_or_cell_type: Mitochondrial ferroptosis defense\nexperimental_model: Genetic and pharmacological cancer-cell studies\nlimitations: Pharmacological attribution and relative DHODH contribution were directly challenged in 2023; preserve the dispute rather than generalizing to dietary CoQ effects.\nexposure: DHODH loss or brequinar, with GPX4 inhibition\nevidence_span: {\"source_cache\": \"artifacts/coq10-research/33981038.abstract.txt\", \"locator\": \"Primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b\", \"start_char\": 0, \"end_char\": 1716, \"text_sha256\": \"b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b\"}\n[coq10-p33981038] DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. (2021). https://pubmed.ncbi.nlm.nih.gov/33981038/ DOI: 10.1038/s41586-021-03539-7","source_key":"import-3b5aff9b-4086-5574-bfb4-3ea49ba520d7","source_title":"Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17)","claim_ids":["82d498e5-6657-5d30-8a01-56bbf34c810c"]},{"conflict_id":"c96a0617-fd29-5a15-a075-d8b1f62f3b1e","ordinal":1,"label":"2023: FSP1 off-target challenge","revision_id":"028900ce-8ca4-5d13-8c86-6e327c071e64","start_line":840,"end_line":851,"quote":"### coq10-dhodh-offtarget\nThe 2023 study attributed strong ferroptosis sensitization by high concentrations of DHODH inhibitors to concurrent FSP1 inhibition.\nCondition category: normal\nnutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: A drug can affect a second enzyme, changing the explanation of its result.\norganism: Cancer-cell inhibitor and genetic comparisons\ntissue_or_cell_type: DHODH versus FSP1 attribution\nexperimental_model: Primary experimental Matters Arising; public publisher preview\nlimitations: Public preview only; exact dose-response tables not extracted. Do not deny all DHODH effects or invent a universal concentration cutoff.\nexposure: DHODH inhibitors at different concentrations\nevidence_span: {\"source_cache\": \"artifacts/coq10-research/37407687.publisher-preview.txt\", \"locator\": \"Primary public publisher preview, reference superscripts removed; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"dd04682c5ac5215eff4a195cf2fcff7c5f6cf59eb659cc5710e6a2ecd09b0529\", \"start_char\": 0, \"end_char\": 477, \"text_sha256\": \"dd04682c5ac5215eff4a195cf2fcff7c5f6cf59eb659cc5710e6a2ecd09b0529\"}\n[coq10-p37407687] DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. (2023). https://pubmed.ncbi.nlm.nih.gov/37407687/ DOI: 10.1038/s41586-023-06269-0","source_key":"import-3b5aff9b-4086-5574-bfb4-3ea49ba520d7","source_title":"Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17)","claim_ids":["ea16fae7-c4b2-57c9-830e-6eb61c969068"]},{"conflict_id":"c96a0617-fd29-5a15-a075-d8b1f62f3b1e","ordinal":2,"label":"2023: authors reply","revision_id":"028900ce-8ca4-5d13-8c86-6e327c071e64","start_line":1282,"end_line":1284,"quote":"### Context for coq10-dhodh-attribution\nThe original authors published a counterargument addressing the magnitude of genetic effects, inhibitor off-target activity and mitochondrial GPX4 interpretation; the public preview does not resolve the quantitative disagreement.\n[coq10-p37407682] Reply to: DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. (2023). https://pubmed.ncbi.nlm.nih.gov/37407682/ DOI: 10.1038/s41586-023-06270-7","claim_id":null,"source_key":"import-3b5aff9b-4086-5574-bfb4-3ea49ba520d7","source_title":"Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17)","claim_ids":[]}]}],"corrections":[],"research":null}