{"id":"c4e860a9-78c0-56d5-98d9-7063fa04ba54","stable_key":"e13b03e1-a614-543a-ac1b-97df18cfe30d:iron-gsh-gpx-loss","predicate":"depletion_inactivates","statement":"Glutathione depletion in response to one class of ferroptosis inducers inactivated glutathione peroxidases, while another class directly inhibited GPX4.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"context_dependent","is_public":true,"mechanism_event_id":"9e67ee2d-8b4c-5cf7-a1b1-bc0f456d9089","mechanism_event_label":"Losing the antioxidant substrate and directly blocking its enzyme are different routes into the same vulnerability.","subject":{"id":"b44c9e27-4bbb-52d3-a022-14cddded5073","slug":"glutathione","display_name":"GSH","entity_type_key":"small_molecule"},"object":{"id":"e9bb13ee-f238-51e6-9101-78ddfd11465c","slug":"gpx4","display_name":"GPX4","entity_type_key":"protein"},"evidence_count":1,"mechanism_event":{"id":"9e67ee2d-8b4c-5cf7-a1b1-bc0f456d9089","stable_key":"e13b03e1-a614-543a-ac1b-97df18cfe30d:iron-gsh-gpx-loss-event","event_type":"biochemical_relationship","label":"Losing the antioxidant substrate and directly blocking its enzyme are different routes into the same vulnerability.","description":"Glutathione depletion in response to one class of ferroptosis inducers inactivated glutathione peroxidases, while another class directly inhibited GPX4.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"b44c9e27-4bbb-52d3-a022-14cddded5073","slug":"glutathione","display_name":"GSH","entity_type_key":"small_molecule"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"e9bb13ee-f238-51e6-9101-78ddfd11465c","slug":"gpx4","display_name":"GPX4","entity_type_key":"protein"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/iron-research/24439385.abstract.txt\", \"locator\": \"Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"f8d588af38ec5438fbec80971ead0764466237b3382492051aa3b3c297841703\", \"start_char\": 0, \"end_char\": 957, \"text_sha256\": \"f8d588af38ec5438fbec80971ead0764466237b3382492051aa3b3c297841703\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Metabolomics, chemoproteomics, perturbation and cancer-cell sensitivity profiling","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Two classes of ferroptosis-inducing compounds","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Preclinical drug-response mechanism; selenium or vitamin E supplementation is not established as a universal treatment.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Iron research collection; topical membership is not evidence of a direct dietary effect.","comparator":null,"unit":null,"notes":"","entity":{"slug":"iron","display_name":"Iron","entity_type_key":"nutrient_element"}},{"dimension":"organism","value_text":"Human cancer-cell lines and mouse xenografts","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Losing the antioxidant substrate and directly blocking its enzyme are different routes into the same vulnerability.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[iron-p24439385] Regulation of ferroptotic cancer cell death by GPX4. (2014). https://pubmed.ncbi.nlm.nih.gov/24439385/ DOI: 10.1016/j.cell.2013.12.010","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Glutathione/GPX4 antioxidant system","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"73406ce3-1a2a-5dba-a1e6-4b280eafaa03","evidence_kind":"source_excerpt","locator":"Lines 1252-1263","start_line":1252,"end_line":1263,"excerpt":"### iron-gsh-gpx-loss\nGlutathione depletion in response to one class of ferroptosis inducers inactivated glutathione peroxidases, while another class directly inhibited GPX4.\nCondition category: normal\nnutrient_topic: Iron research collection; topical membership is not evidence of a direct dietary effect.\nplain_language: Losing the antioxidant substrate and directly blocking its enzyme are different routes into the same vulnerability.\norganism: Human cancer-cell lines and mouse xenografts\ntissue_or_cell_type: Glutathione/GPX4 antioxidant system\nexperimental_model: Metabolomics, chemoproteomics, perturbation and cancer-cell sensitivity profiling\nlimitations: Preclinical drug-response mechanism; selenium or vitamin E supplementation is not established as a universal treatment.\nexposure: Two classes of ferroptosis-inducing compounds\nevidence_span: {\"source_cache\": \"artifacts/iron-research/24439385.abstract.txt\", \"locator\": \"Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"f8d588af38ec5438fbec80971ead0764466237b3382492051aa3b3c297841703\", \"start_char\": 0, \"end_char\": 957, \"text_sha256\": \"f8d588af38ec5438fbec80971ead0764466237b3382492051aa3b3c297841703\"}\n[iron-p24439385] Regulation of ferroptotic cancer cell death by GPX4. 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