{"id":"ceb73a97-8277-58f7-b633-c7ee0685f478","stable_key":"74ef5bba-ee14-531c-b1bf-d1f297c56bb6:fisetin-gpx4-block-metal-injury","predicate":"worsens","statement":"With RSL3-mediated GPX4 inhibition, 5 micromolar fisetin enhanced iron-potentiated HT22 toxicity at iron concentrations of 2.5 micromolar or higher.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"482d5c80-8cbc-50c8-8a54-d96285f34ba5","mechanism_event_label":"Protection can fail when a different defense step is blocked.","subject":{"id":"dee05061-c3f3-5226-8054-dd58b76a585d","slug":"fisetin","display_name":"Fisetin","entity_type_key":"small_molecule"},"object":{"id":"42b1d7b8-0964-536a-b834-e4205e71062d","slug":"mouse-ht22-rsl3-iron-injury","display_name":"Mouse HT22 injury during RSL3 plus iron exposure","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"482d5c80-8cbc-50c8-8a54-d96285f34ba5","stable_key":"74ef5bba-ee14-531c-b1bf-d1f297c56bb6:fisetin-gpx4-block-metal-injury-event","event_type":"observed_relationship","label":"Protection can fail when a different defense step is blocked.","description":"With RSL3-mediated GPX4 inhibition, 5 micromolar fisetin enhanced iron-potentiated HT22 toxicity at iron concentrations of 2.5 micromolar or higher.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"dee05061-c3f3-5226-8054-dd58b76a585d","slug":"fisetin","display_name":"Fisetin","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"42b1d7b8-0964-536a-b834-e4205e71062d","slug":"mouse-ht22-rsl3-iron-injury","display_name":"Mouse HT22 injury during RSL3 plus iron exposure","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"3b4daaa3-efad-5cef-83ff-f30647d97485","slug":"rsl3","display_name":"RSL3 / experimental GPX4 inhibitor","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"50cfff80-f853-55e4-bb4b-ec4c600b5c7a","slug":"mouse-gpx4","display_name":"Mouse glutathione peroxidase 4 / Gpx4","entity_type_key":"protein"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"59d6d1cd-df32-5b58-b950-3188bc7b95d6","slug":"iron-ii","display_name":"Ferrous iron","entity_type_key":"ion"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"b44c9e27-4bbb-52d3-a022-14cddded5073","slug":"glutathione","display_name":"GSH","entity_type_key":"small_molecule"},"role":"context_participant","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_access","value_text":"Primary full text","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Mouse cells; pharmacological GPX4 inhibition plus iron.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Not proof that fisetin worsens ordinary selenium deficiency; RSL3 and dietary selenium shortage differ.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit.","comparator":null,"unit":null,"notes":"","entity":{"slug":"fisetin","display_name":"Fisetin","entity_type_key":"small_molecule"}},{"dimension":"plain_language","value_text":"Protection can fail when a different defense step is blocked.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"f2530792-e605-57b4-8c59-60ef4079c2fc","evidence_kind":"source_excerpt","locator":"Lines 168-174","start_line":168,"end_line":174,"excerpt":"## fisetin-gpx4-block-metal-injury\nProtection can fail when a different defense step is blocked.\nWith RSL3-mediated GPX4 inhibition, 5 micromolar fisetin enhanced iron-potentiated HT22 toxicity at iron concentrations of 2.5 micromolar or higher.\nModel: Mouse cells; pharmacological GPX4 inhibition plus iron.\nLimitations: Not proof that fisetin worsens ordinary selenium deficiency; RSL3 and dietary selenium shortage differ.\nEvidence access: Primary full text\nModulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113","model_system":"Mouse cells; pharmacological GPX4 inhibition plus iron.","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":"1108bfff-6504-5152-a51f-ff3d7c27c282","stable_key":"import-74ef5bba-ee14-531c-b1bf-d1f297c56bb6","title":"Fisetin: metabolism, cell-state responses 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":"c30e0764cd34bd062cfcbfaf32357ef29dfda30e7d4153c545178140f5054e09","revision_id":"40ff52c0-f4b9-5820-8abb-ff002c6364a4","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[],"corrections":[],"research":null}