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Neutrophils are a plausible target of this transition because their antimicrobial functions depend on tightly organized redox reactions, whereas their short lifespan and limited biosynthetic reserve may restrict adaptation to metal stress.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Recent Advances:<\/jats:title>\n                    <jats:p>\n                      This review develops a unified framework in which copper dyshomeostasis first reshapes intracellular copper pools, antioxidant buffering, reduced nicotinamide adenine dinucleotide phosphate\u2013dependent redox metabolism, and mitochondrial signaling; these metabolic disturbances then lower the threshold for several copper-associated cell-death programs; and the combined lesions alter granulopoiesis, chemotaxis, phagocytic killing, neutrophil extracellular trap formation, survival, and inflammatory resolution. Canonical ferredoxin 1\u2013dihydrolipoamide\n                      <jats:italic toggle=\"yes\">S<\/jats:italic>\n                      -acetyltransferase\u2013dependent cuproptosis is treated as a testable, but not yet established, mechanism in mature neutrophils. Stronger evidence supports a broader spectrum of copper-induced injury that includes mitochondrial apoptosis, inflammasome-associated pyroptotic signaling, lipid peroxidation with ferroptosis-like features, and dysregulated neutrophil extracellular trap formation (NETosis).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Critical Issues:<\/jats:title>\n                    <jats:p>The inflammatory outcome of neutrophil death cannot be inferred from cell loss alone: Efficiently cleared apoptotic or early ferroptotic cells may contract the functional neutrophil pool, whereas lytic death, late membrane rupture, defective efferocytosis, and release of oxidized lipids, chromatin, histones, or granular proteins may amplify local inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Future Directions:<\/jats:title>\n                    <jats:p>\n                      By tracing individual routes from copper-pool disruption to defined cellular and tissue-level outcomes, this model distinguishes systemic copper overload from inflammatory copper redistribution and identifies the measurements required to establish copper-dependent neutrophil pathology in human disease.\n                      <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                      00, 000\u2013000.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15230864261489976","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T01:35:54Z","timestamp":1789954554000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["A Unified Mechanistic Framework for Copper Toxicity in Neutrophils: Metabolic Rewiring, Cell-Death Crosstalk, and Immune Dysfunction"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1991-8871","authenticated-orcid":false,"given":"Rui","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Kidney Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China."},{"name":"Shanghai Key Laboratory of Organ Transplantation, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyue","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China."},{"name":"Shanghai Key Laboratory of Organ Transplantation, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Organ Transplantation, Shanghai, China."},{"name":"Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China."},{"name":"Shanghai Key Laboratory of Organ Transplantation, Shanghai, China."},{"name":"Shanghai Medical College, Fudan University, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China."},{"name":"Shanghai Key Laboratory of Organ Transplantation, Shanghai, China."},{"name":"Zhangjiang Institute of Fudan University, Shanghai, China."},{"name":"Shanghai Institute of Medical Imaging, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"e_1_3_3_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0042984"},{"key":"e_1_3_3_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathmechdis-051222-015009"},{"key":"e_1_3_3_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00550-8"},{"key":"e_1_3_3_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.3.1002"},{"key":"e_1_3_3_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01229-y"},{"key":"e_1_3_3_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02599"},{"key":"e_1_3_3_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2025.103795"},{"key":"e_1_3_3_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03021"},{"key":"e_1_3_3_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2017.1368505"},{"key":"e_1_3_3_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-016-1000-7"},{"key":"e_1_3_3_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2023.101849"},{"key":"e_1_3_3_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2026.116955"},{"key":"e_1_3_3_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13186"},{"key":"e_1_3_3_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/jleuko\/qiae057"},{"key":"e_1_3_3_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/mtomcs\/mfad040"},{"key":"e_1_3_3_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2011.09.040"},{"key":"e_1_3_3_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10640"},{"key":"e_1_3_3_19_1","doi-asserted-by":"publisher","DOI":"10.4161\/cib.3.3.11559"},{"key":"e_1_3_3_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.04.013"},{"issue":"4","key":"e_1_3_3_21_1","first-page":"195","article-title":"Anemia and neutropenia in a case of copper deficiency: Role of copper in normal hematopoiesis","volume":"87","author":"Hirase N","year":"1992","unstructured":"Hirase N, , Abe Y, , Sadamura S, et al. 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