{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:48:49Z","timestamp":1782953329318,"version":"3.54.5"},"reference-count":146,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32060289"],"award-info":[{"award-number":["32060289"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171610"],"award-info":[{"award-number":["32171610"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004775","name":"Natural Science Foundation of Gansu Province","doi-asserted-by":"publisher","award":["21JR7RA365"],"award-info":[{"award-number":["21JR7RA365"]}],"id":[{"id":"10.13039\/501100004775","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004775","name":"Natural Science Foundation of Gansu Province","doi-asserted-by":"publisher","award":["25JRRA1260"],"award-info":[{"award-number":["25JRRA1260"]}],"id":[{"id":"10.13039\/501100004775","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cadmium (Cd) is a globally persistent toxic metal with extraordinary biological retention and cumulative tissue toxicity. Ferroptosis has emerged as a proposed mechanism of Cd\u2010induced cytotoxicity. However, current research is characterized by profound methodological heterogeneity, supraphysiological dosing, incomplete ferroptosis validation, overlapping cell death pathways, and inconsistent mechanistic interpretations. Here, we perform a systematic, mechanism\u2010centered, and dose\u2010aware critical review of Cd\u2010induced ferroptosis, based on a newly established four\u2010tier causality framework that distinguishes genuine ferroptosis from non\u2010specific oxidative injury. We integrate existing data into three mechanistic axes: LIP expansion via ferritinophagy, dysregulation of the Nrf2\/SLC7A11\/GPX4 antioxidant defense system, and mtROS amplification. At the same time, we highlight two major mechanistic paradoxes: the HO\u20101 functional switch and the dose\u2010duration discrepancy. Based on a critical review of all available data, current data do not support ferroptosis as a universal mechanism of Cd toxicity. Instead, it is a context\u2010 and dose\u2010dependent phenomenon that appears to become most prominent under acute high\u2010dose exposure conditions. Finally, we propose a comprehensive research roadmap including physiologically realistic exposure models, establishment of ferroptosis\u2010specific validation standards, ferroptosis biomarker development, and mechanistic resolution of the HO\u20101 and dose\u2010duration paradoxes. This work aims to refine conceptual oversimplifications, address methodological weaknesses, and establish a rigorous toxicological foundation for future research.<\/jats:p>","DOI":"10.1002\/jat.70311","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:30:33Z","timestamp":1782952233000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cadmium\u2010Induced Ferroptosis: Critical Evidence Assessment, Mechanistic Paradoxes, Dose Realism, and Translational Gaps in Toxicological Research"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7548-9918","authenticated-orcid":false,"given":"Boyuan","family":"Wang","sequence":"first","affiliation":[{"name":"The First Clinical Medical College of Lanzhou University  Lanzhou Gansu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Tang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College of Lanzhou University  Lanzhou Gansu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honglong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery Union Hospital, Tongji Medical College, Huazhong University of Science and Technology  Wuhan People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenxiu","family":"Jiang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College of Lanzhou University  Lanzhou Gansu People's Republic of China"},{"name":"The Department of Neurology The First Hospital of Lanzhou University  Lanzhou Gansu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yan","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College of Lanzhou University  Lanzhou Gansu People's Republic of China"},{"name":"Department of General Surgery The First Hospital of Lanzhou University  Lanzhou Gansu People's Republic of China"},{"name":"Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province  Lanzhou Gansu People's Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"issue":"1","key":"e_1_2_14_2_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41392-024-02088-5","article-title":"In Defence of Ferroptosis","volume":"10","author":"Alves F.","year":"2025","journal-title":"Signal Transduction and Targeted Therapy"},{"issue":"9","key":"e_1_2_14_3_1","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1007\/s00204-022-03317-y","article-title":"Ferroptosis as a Mechanism of Non\u2010Ferrous Metal Toxicity","volume":"96","author":"Aschner M.","year":"2022","journal-title":"Archives of Toxicology"},{"issue":"2","key":"e_1_2_14_4_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41380-022-01568-w","article-title":"Apolipoprotein E Potently Inhibits Ferroptosis by Blocking Ferritinophagy","volume":"29","author":"Belaidi A. A.","year":"2024","journal-title":"Molecular Psychiatry"},{"issue":"5","key":"e_1_2_14_5_1","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1016\/j.bbamcr.2018.02.010","article-title":"Nrf2\u2010Keap1 Signaling in Oxidative and Reductive Stress","volume":"1865","author":"Bellezza I.","year":"2018","journal-title":"Biochimica et Biophysica Acta, Molecular Cell Research"},{"issue":"45","key":"e_1_2_14_6_1","doi-asserted-by":"crossref","first-page":"39387","DOI":"10.1074\/jbc.M111.279893","article-title":"Translocation of Heme Oxygenase\u20101 to Mitochondria Is a Novel Cytoprotective Mechanism Against Non\u2010Steroidal Anti\u2010Inflammatory Drug\u2010Induced Mitochondrial Oxidative Stress, Apoptosis, and Gastric Mucosal Injury","volume":"286","author":"Bindu S.","year":"2011","journal-title":"Journal of Biological Chemistry"},{"key":"e_1_2_14_7_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.phrs.2020.105297","article-title":"Necrostatin\u20101 and Necroptosis Inhibition: Pathophysiology and Therapeutic Implications","volume":"163","author":"Cao L.","year":"2021","journal-title":"Pharmacological Research"},{"key":"e_1_2_14_8_1","doi-asserted-by":"crossref","first-page":"128346","DOI":"10.1016\/j.chemosphere.2020.128346","article-title":"Cadmium Induced BEAS\u20102B Cells Apoptosis and Mitochondria Damage via MAPK Signaling Pathway","volume":"263","author":"Cao X.","year":"2021","journal-title":"Chemosphere"},{"issue":"18","key":"e_1_2_14_9_1","doi-asserted-by":"crossref","DOI":"10.3390\/molecules28186620","article-title":"Cadmium Toxicity and Health Effects\u2010A Brief Summary","volume":"28","author":"Charkiewicz A. 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