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Ferroptosis is driven by iron-dependent phospholipid peroxidation when glutathione peroxidase 4 (GPX4)-dependent and parallel antioxidant systems fail, whereas cuproptosis depends on mitochondrial copper engagement of lipoylated tricarboxylic-acid-cycle proteins, lipoylated-protein aggregation, iron\u2013sulfur protein destabilization, and proteotoxic stress. This review integrates the molecular basis, genetic architecture, long non-coding RNA (lncRNA)-mediated regulation, mechanistic crosstalk, and therapeutic implications of ferroptosis and cuproptosis in cancer. It emphasizes a critical evidence hierarchy: expression association, computational signature construction, metal accumulation, reactive oxygen species (ROS) generation, or reduced viability should not be interpreted as pathway dependency without pathway-defining biochemical endpoints and rescue experiments. The most credible translational opportunities will depend on functional stratification, tumour-selective delivery, and pharmacodynamic confirmation that distinguishes pathway-defined ferroptosis or cuproptosis from nonspecific metal-induced and oxidative cytotoxicity.<\/jats:p>","DOI":"10.3390\/cells15151421","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:16:29Z","timestamp":1785935789000},"page":"1421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["From Metal Stress to Regulated Cell Death: An Evidence Framework for Ferroptosis\u2013Cuproptosis Crosstalk in Cancer"],"prefix":"10.3390","volume":"15","author":[{"given":"Andrada-Adelaida","family":"Belbe","sequence":"first","affiliation":[{"name":"Department of Molecular Sciences, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0975-5200","authenticated-orcid":false,"given":"Lorin-Manuel","family":"P\u00eerlog","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Department of Medical Genetics, Clinical Emergency Hospital for Children, 400370 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Spori\u0219","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Clinical Emergency Hospital for Children, 400370 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adela-Diana","family":"Pitforodeschi","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissia-Nicoleta","family":"Pilatec","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rare\u0219-Mihai","family":"B\u0103il\u0103","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Rusu","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mihaela Amelia","family":"Dobrescu","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University of Medicine and Pharmacy of Craiova, 2, Petru Rare\u0219 St., 200349 Craiova, Romania"},{"name":"Regional Centre of Medical Genetics Dolj, Emergency County Hospital Craiova, 200642 Craiova, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariela-Sanda","family":"Militaru","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Regional Laboratory Cluj-Napoca, Department of Medical Genetics, Regina Maria Health Private Network, 400363 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina-Ioana","family":"Iord\u0103nescu","sequence":"additional","affiliation":[{"name":"Genetic Centre Laboratory, Department of Medical Genetics, Regina Maria Health Private Network, 011376 Bucharest, Romania"},{"name":"Genetics Department, \u201cCarol Davila\u201d University of Medicine and Pharmacy, 020027 Bucharest, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreea","family":"C\u0103tan\u0103","sequence":"additional","affiliation":[{"name":"Department of Molecular Sciences, Faculty of Medicine, \u201cIuliu Ha\u021bieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Regional Laboratory Cluj-Napoca, Department of Medical Genetics, Regina Maria Health Private Network, 400363 Cluj-Napoca, Romania"},{"name":"Department of Oncogenetics, \u201cProf. Dr. I. 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