{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T13:18:40Z","timestamp":1786195120493,"version":"build-2736575974"},"reference-count":74,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T00:00:00Z","timestamp":1782604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic oxidative stress is a molecular hallmark of cardiovascular\u2013kidney\u2013metabolic (CKM) syndrome, yet its contribution to CKM-associated anemia beyond erythropoietin deficiency and iron restriction is poorly characterized. The serum copper-to-zinc (Cu\/Zn) ratio reflects impaired Cu\/Zn-SOD1 antioxidant capacity and inflammatory trace-element imbalance, but its relationships with circulating redox biomarkers and its hematological relevance in CKM syndrome has never been explored in a community-dwelling cohort of older adults. We analyzed 2391 NHANES 2011\u20132016 participants \u2265 50 years of age with CKM stage I-IV. To explore whether the serum Cu\/Zn ratio was associated with oxidative stress and immunomodulatory biomarkers as well as with the odds of anemia, we used survey-weighted Spearman correlations, linear regression (outcome: hemoglobin), and logistic regression (outcome: anemia); multivariate models were adjusted for a panel of antioxidant or immunomodulatory biomarkers (selenium, vitamin D), pro-oxidant biomarkers (lead, cadmium, cotinine, uric acid), red cell distribution width (RDW) as a composite biomarker of erythrocyte stress, neutrophil-to-lymphocyte ratio (NLR), CKM stage, and comorbidities. The molecular targets of the nine biomarkers were mapped onto a protein\u2013protein interaction network using the STRING database v12.0 to contextualize regression findings within a systems biology framework. Anemia was present in 205 participants (8.6%). The Cu\/Zn ratio was inversely correlated with the antioxidant marker selenium (r = \u22120.19; p &lt; 0.001) and positively correlated with the pro-oxidant markers RDW (r = +0.21; p &lt; 0.001) and cadmium (r = +0.10; p &lt; 0.001), consistent with its role as a hub within the CKM redox network. In fully adjusted models, a higher Cu\/Zn ratio was independently associated with prevalent anemia (OR = 2.94; 95% CI: 1.61\u20135.37) and lower hemoglobin (\u03b2 = \u22120.55 g\/dL); among included biomarkers, selenium and cadmium were independently protective (OR = 0.76 per 10 \u00b5g\/L and 0.23 per \u00b5g\/dL, respectively), and RDW and uric acid were independently harmful (OR = 2.20 per 1% and 1.33 per mg\/dL, respectively). The Cu\/Zn ratio correlated with both antioxidant depletion and pro-oxidant accumulation in CKM syndrome and was independently associated with anemia within this oxidative network. Together with selenium, cadmium, RDW, and uric acid, it defines an oxidative stress-driven hematological pathway that may contribute to the development and progression of anemia in patients with CKM syndrome.<\/jats:p>","DOI":"10.3390\/ijms27135840","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:55:11Z","timestamp":1782780911000},"page":"5840","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Serum Copper-to-Zinc Ratio and Oxidative Stress Are Associated with Anemia in Older Adults with Cardiovascular\u2013Kidney\u2013Metabolic Syndrome"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9065-4467","authenticated-orcid":false,"given":"Giuseppe","family":"Bruschetta","sequence":"first","affiliation":[{"name":"Biochemistry Unit, Department of Veterinary Sciences, University of Messina, Viale Palatucci, 13, 98168 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4823-9910","authenticated-orcid":false,"given":"Guido","family":"Gembillo","sequence":"additional","affiliation":[{"name":"Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 90125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9112-5540","authenticated-orcid":false,"given":"Lorenzo","family":"Lo Cicero","sequence":"additional","affiliation":[{"name":"Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 90125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7530-1316","authenticated-orcid":false,"given":"Angela","family":"D\u2019Ascola","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Messina, Policlinico Universitario, Via Consolare Valeria 1, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7263-803X","authenticated-orcid":false,"given":"Fabio","family":"Bruno","sequence":"additional","affiliation":[{"name":"Biochemistry Unit, Department of Veterinary Sciences, University of Messina, Viale Palatucci, 13, 98168 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7276-3256","authenticated-orcid":false,"given":"Andrea","family":"Corsonello","sequence":"additional","affiliation":[{"name":"Unit of Geriatric Medicine and Clinical Epidemiology, INRCA IRCCS, Cda Muoio Piccolo, 87100 Cosenza, Italy"},{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, 87036 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Santoro","sequence":"additional","affiliation":[{"name":"Unit of Nephrology and Dialysis, Department of Clinical and Experimental Medicine, University of Messina, 90125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1862-4159","authenticated-orcid":false,"given":"Mirko","family":"Di Rosa","sequence":"additional","affiliation":[{"name":"Unit of Geriatric Medicine and Clinical Epidemiology, INRCA IRCCS, Cda Muoio Piccolo, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0171-3358","authenticated-orcid":false,"given":"Luca","family":"Soraci","sequence":"additional","affiliation":[{"name":"Unit of Geriatric Medicine and Clinical Epidemiology, INRCA IRCCS, Cda Muoio Piccolo, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1161\/CIR.0000000000001186","article-title":"A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association","volume":"148","author":"Ndumele","year":"2023","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1161\/CIR.0000000000001184","article-title":"Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association","volume":"148","author":"Ndumele","year":"2023","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.1001\/jama.2024.6892","article-title":"Prevalence of Cardiovascular-Kidney-Metabolic Syndrome Stages in US Adults, 2011\u20132020","volume":"331","author":"Aggarwal","year":"2024","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1824","DOI":"10.1016\/j.jacc.2024.03.368","article-title":"Prevalence of the Cardiovascular-Kidney-Metabolic Syndrome in the United States","volume":"83","author":"Minhas","year":"2024","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1159\/000546618","article-title":"Associations of Cardiovascular-Kidney-Metabolic Syndrome with Premature Mortality and Life Expectancies in US Adults: A Cohort Study","volume":"15","author":"Lei","year":"2025","journal-title":"Cardiorenal Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1007\/s11906-012-0279-2","article-title":"Oxidative stress in the cardiorenal metabolic syndrome","volume":"14","author":"Sowers","year":"2012","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Roumeliotis, S., Neofytou, I.E., Roumeliotis, A., Veljkovic, A., Cojic, M., and Kocic, G. (2025). Association of Oxidative Stress Markers with Cardio-Kidney-Metabolic Parameters and Cardiovascular Disease in Patients with Type 2 Diabetes Mellitus. Biomolecules, 16.","DOI":"10.3390\/biom16010042"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6039","DOI":"10.1007\/s11010-025-05379-9","article-title":"Inflammation in cardiovascular-kidney-metabolic syndrome: Key roles and underlying mechanisms-a comprehensive review","volume":"480","author":"Xu","year":"2025","journal-title":"Mol. Cell. Biochem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3298","DOI":"10.3390\/ijms25063298","article-title":"The Renin-Angiotensin System and Cardiovascular-Kidney-Metabolic Syndrome: Focus on Early-Life Programming","volume":"25","author":"Tain","year":"2024","journal-title":"Int. J. Mol. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.3390\/cancers17071169","article-title":"In the Era of Cardiovascular-Kidney-Metabolic Syndrome in Cardio-Oncology: From Pathogenesis to Prevention and Therapy","volume":"17","author":"Quagliariello","year":"2025","journal-title":"Cancers"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1186\/s12933-023-01937-x","article-title":"The cardio-renal-metabolic connection: A review of the evidence","volume":"22","author":"Marassi","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.arcmed.2013.11.002","article-title":"The AGE-RAGE pathway and its relation to cardiovascular disease in patients with chronic kidney disease","volume":"44","author":"Leurs","year":"2013","journal-title":"Arch. Med. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4120","DOI":"10.3390\/ijms27094120","article-title":"Mitochondrial Dysfunction at the Intersection of CKM Syndrome: Molecular Mechanisms and Path-to-Target Therapies","volume":"27","author":"Kuo","year":"2026","journal-title":"Int. J. Mol. Sci."},{"key":"ref_14","first-page":"S4","article-title":"Piecing together the evidence on anemia: The link between chronic kidney disease and cardiovascular disease","volume":"6","author":"McCullough","year":"2005","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1053\/j.ajkd.2014.12.016","article-title":"Cardiorenal Syndrome and the Role of the Bone-Mineral Axis and Anemia","volume":"66","author":"Charytan","year":"2015","journal-title":"Am. J. Kidney Dis."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Theodorakis, N., and Nikolaou, M. (2025). From Cardiovascular-Kidney-Metabolic Syndrome to Cardiovascular-Renal-Hepatic-Metabolic Syndrome: Proposing an Expanded Framework. Biomolecules, 15.","DOI":"10.3390\/biom15020213"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hamza, E., Metzinger, L., and Metzinger-Le Meuth, V. (2020). Uremic Toxins Affect Erythropoiesis during the Course of Chronic Kidney Disease: A Review. Cells, 9.","DOI":"10.3390\/cells9092039"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1172\/JCI200420945","article-title":"IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin","volume":"113","author":"Nemeth","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"(2026). KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease (CKD). Kidney Int., 109, S1\u2013S99.","DOI":"10.1016\/j.kint.2025.06.006"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1681\/ASN.2011111078","article-title":"Mechanisms of anemia in CKD","volume":"23","author":"Babitt","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s10522-009-9251-1","article-title":"Plasma copper\/zinc ratio: An inflammatory\/nutritional biomarker as predictor of all-cause mortality in elderly population","volume":"11","author":"Malavolta","year":"2010","journal-title":"Biogerontology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.mad.2015.01.004","article-title":"Serum copper to zinc ratio: Relationship with aging and health status","volume":"151","author":"Malavolta","year":"2015","journal-title":"Mech. Ageing Dev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9215","DOI":"10.1002\/anie.202000451","article-title":"Superoxide Dismutase 1 in Health and Disease: How\u2009a\u2009Frontline Antioxidant Becomes Neurotoxic","volume":"60","author":"Trist","year":"2021","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.1074\/jbc.TM117.000182","article-title":"Eukaryotic copper-only superoxide dismutases (SODs): A new class of SOD enzymes and SOD-like protein domains","volume":"293","author":"Robinett","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1096\/fj.04-2450fje","article-title":"Peroxynitrite induces senescence and apoptosis of red blood cells through the activation of aspartyl and cysteinyl proteases","volume":"19","author":"Matarrese","year":"2005","journal-title":"FASEB J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/jdi.13659","article-title":"Synergistic association of the copper\/zinc ratio under inflammatory conditions with diabetic kidney disease in patients with type 2 diabetes: The Asahi Diabetes Complications Study","volume":"13","author":"Takao","year":"2022","journal-title":"J. Diabetes Investig."},{"key":"ref_27","first-page":"e88573","article-title":"Copper\/Zinc Ratio as a Predictor of Chronic Kidney Disease Incidence in Type 2 Diabetes: The Asahi Diabetes Complications Study","volume":"17","author":"Takao","year":"2025","journal-title":"Cureus"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1007\/s12011-021-02888-8","article-title":"Association Between the Blood Copper-Zinc (Cu\/Zn) Ratio and Anemia in Patients Undergoing Maintenance Hemodialysis","volume":"200","author":"Zuo","year":"2022","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1002\/ehf2.14893","article-title":"Role of selenium in the pathophysiology of cardiorenal anaemia syndrome","volume":"12","author":"Arai","year":"2025","journal-title":"ESC Heart Fail."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/S0946-672X(97)80002-8","article-title":"Cadmium-induced lipid peroxidation and the antioxidant system in rat erythrocytes: The role of antioxidants","volume":"11","author":"Sarkar","year":"1997","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cca.2007.04.024","article-title":"Low level lead exposure and oxidative stress: Current opinions","volume":"383","author":"Ahamed","year":"2007","journal-title":"Clin. Chim. Acta"},{"key":"ref_32","first-page":"40","article-title":"Cigarette smoking and antioxidant defences in packed red blood cells prior to storage","volume":"18","author":"Boehm","year":"2020","journal-title":"Blood Transfus."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3109\/10408363.2014.992064","article-title":"Red blood cell distribution width: A simple parameter with multiple clinical applications","volume":"52","author":"Salvagno","year":"2015","journal-title":"Crit. Rev. Clin. Lab. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, Y., Ming, J., Guo, Z., Zhang, W., Li, X., Zhou, S., Li, X., and Ma, H. (2023). Association of serum uric acid with anemia in U.S. adults: A cross-sectional study using secondary data. BMC Cardiovasc. Disord., 23.","DOI":"10.1186\/s12872-023-03291-y"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1073\/pnas.87.8.3137","article-title":"Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocyte monolayer cultures","volume":"87","author":"Schroeder","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.molbrainres.2005.05.027","article-title":"Transcriptional regulation of ceruloplasmin by an IL-6 response element pathway","volume":"139","author":"Conley","year":"2005","journal-title":"Brain Res. Mol. Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1093\/jn\/118.12.1436","article-title":"Nutritional aspects of leukocytic cytokines","volume":"118","author":"Klasing","year":"1988","journal-title":"J. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"398","DOI":"10.34067\/KID.0007812021","article-title":"Zinc Deficiency: A Potential Hidden Driver of the Detrimental Cycle of Chronic Kidney Disease and Hypertension","volume":"4","author":"Ume","year":"2023","journal-title":"Kidney360"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Nakatani, S., Morioka, T., Morioka, F., Mori, K., and Emoto, M. (2025). Zinc Deficiency in Chronic Kidney Disease and Hemodialysis: Insights from Basic Research to Clinical Implications. Nutrients, 17.","DOI":"10.3390\/nu17132191"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lor\u00e9al, O., Cavey, T., Bardou-Jacquet, E., Guggenbuhl, P., Ropert, M., and Brissot, P. (2014). Iron, hepcidin, and the metal connection. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00128"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1152\/physrev.00004.2006","article-title":"Function and regulation of human copper-transporting ATPases","volume":"87","author":"Lutsenko","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.cmet.2005.10.003","article-title":"Unexpected role of ceruloplasmin in intestinal iron absorption","volume":"2","author":"Cherukuri","year":"2005","journal-title":"Cell Metab."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Fuqua, B.K., Lu, Y., Darshan, D., Frazer, D.M., Wilkins, S.J., Wolkow, N., Bell, A.G., Hsu, J., Yu, C.C., and Chen, H. (2014). The multicopper ferroxidase hephaestin enhances intestinal iron absorption in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098792"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.1182\/blood-2016-09-687889","article-title":"GATA factor mutations in hematologic disease","volume":"129","author":"Crispino","year":"2017","journal-title":"Blood"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/978-3-031-62731-6_10","article-title":"Erythroid Kr\u00fcppel-Like Factor (KLF1): A Surprisingly Versatile Regulator of Erythroid Differentiation","volume":"1459","author":"Bieker","year":"2024","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/375318a0","article-title":"Lethal beta-thalassaemia in mice lacking the erythroid CACCC-transcription factor EKLF","volume":"375","author":"Perkins","year":"1995","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"19055","DOI":"10.1038\/s41598-020-76118-x","article-title":"Inhibition of red blood cell development by arsenic-induced disruption of GATA-1","volume":"10","author":"Zhou","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Hagele, A., Hanson, Z., Borecky, M., Fay, A., Mirshahidi, S., Boghossian, R., Dermarderosian, A., and Akhtari, M. (2026). Zinc deficiency and chronic anemia: A retrospective analysis of zinc supplementation in populations with concurrent nutritional and clinical risk factors. J. Investig. Med., 10815589261422251.","DOI":"10.1177\/10815589261422251"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"101746","DOI":"10.1016\/j.redox.2020.101746","article-title":"Copper interferes with selenoprotein synthesis and activity","volume":"37","author":"Schwarz","year":"2020","journal-title":"Redox Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"120521","DOI":"10.1016\/j.atherosclerosis.2025.120521","article-title":"Association between cardiovascular-kidney-metabolic syndrome, inflammatory biomarkers, and cardiovascular outcomes: Insights from the MESA study","volume":"410","author":"Ahmad","year":"2025","journal-title":"Atherosclerosis"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1016\/j.bbagen.2012.11.020","article-title":"Glutathione peroxidases","volume":"1830","author":"Maiorino","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1172\/JCI112196","article-title":"Effect of hydrogen peroxide exposure on normal human erythrocyte deformability, morphology, surface characteristics, and spectrin-hemoglobin cross-linking","volume":"76","author":"Snyder","year":"1985","journal-title":"J. Clin. Investig."},{"key":"ref_53","first-page":"100020","article-title":"GPX4 regulates lipid peroxidation and ferroptosis of stored red blood cells","volume":"1","author":"Stephenson","year":"2025","journal-title":"Blood"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/0005-2760(82)90150-3","article-title":"Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides","volume":"710","author":"Ursini","year":"1982","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"513518","DOI":"10.1155\/2015\/513518","article-title":"Triggers, inhibitors, mechanisms, and significance of eryptosis: The suicidal erythrocyte death","volume":"2015","author":"Lang","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1159\/000334163","article-title":"Mechanisms and significance of eryptosis, the suicidal death of erythrocytes","volume":"33","author":"Lang","year":"2012","journal-title":"Blood Purif."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Barbarani, G., Fugazza, C., Strouboulis, J., and Ronchi, A.E. (2019). The Pleiotropic Effects of GATA1 and KLF1 in Physiological Erythropoiesis and in Dyserythropoietic Disorders. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00091"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Cant\u00fa, I., Van De Werken, H.J.G., Gillemans, N., Stadhouders, R., Heshusius, S., Maas, A., Esteghamat, F., Ozgur, Z., Van Ijcken, W.F.J., and Grosveld, F. (2019). The mouse KLF1 Nan variant impairs nuclear condensation and erythroid maturation. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0208659"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Pagani, A., Nai, A., Silvestri, L., and Camaschella, C. (2019). Hepcidin and Anemia: A Tight Relationship. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01294"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0742-8413(87)90133-2","article-title":"Displacement of zinc and copper from copper-induced metallothionein by cadmium and by mercury: In vivo and ex vivo studies","volume":"86","author":"Funk","year":"1987","journal-title":"Comp. Biochem. Physiol. C Comp. Pharmacol. Toxicol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Kim, K., Melough, M.M., Vance, T.M., Noh, H., Koo, S.I., and Chun, O.K. (2018). Dietary Cadmium Intake and Sources in the US. Nutrients, 11.","DOI":"10.3390\/nu11010002"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Nuhu, F., and Bhandari, S. (2018). Oxidative Stress and Cardiovascular Complications in Chronic Kidney Disease, the Impact of Anaemia. Pharmaceuticals, 11.","DOI":"10.3390\/ph11040103"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Nelson, K.L., and Voruganti, V.S. (2025). Implication of xanthine oxidoreductase in oxidative stress-related chronic diseases. Front. Endocrinol., 16.","DOI":"10.3389\/fendo.2025.1662037"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3527579","DOI":"10.1155\/2016\/3527579","article-title":"Xanthine Oxidoreductase-Derived Reactive Species: Physiological and Pathological Effects","volume":"2016","author":"Battelli","year":"2016","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1470380","DOI":"10.1155\/2021\/1470380","article-title":"The Role of Oxidative Stress in Hyperuricemia and Xanthine Oxidoreductase (XOR) Inhibitors","volume":"2021","author":"Liu","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"20251181","DOI":"10.1515\/med-2025-1181","article-title":"Effect of smoking and smoking cessation on hematological parameters in polycythemic patients","volume":"20","author":"Ilkkilic","year":"2025","journal-title":"Open Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMra041809","article-title":"Anemia of chronic disease","volume":"352","author":"Weiss","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_68","unstructured":"(2026, June 01). Laboratory Procedure Manual. Analytes: Cadmium, Lead, Manganese, Mercury, and Selenium, Available online: https:\/\/wwwn.cdc.gov\/nchs\/data\/nhanes\/public\/2021\/labmethods\/PBCD-L-MET-508.pdf."},{"key":"ref_69","unstructured":"World Health Organization (2026, June 01). Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Available online: https:\/\/www.who.int\/publications\/i\/item\/WHO-NMH-NHD-MNM-11.1."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1056\/NEJMoa2102953","article-title":"New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race","volume":"385","author":"Inker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_71","unstructured":"National Health and Nutrition Examination Survey (2026, June 01). 2013\u20132014 Data Documentation, Codebook, and Frequencies, Available online: https:\/\/wwwn.cdc.gov\/Nchs\/Data\/Nhanes\/Public\/2013\/DataFiles\/CUSEZN_H.htm."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Mayne, K.J., Walker, H., Elyan, B.M.P., Mark, P.B., Welsh, P., Lang, N.N., Sattar, N.A., Pell, J.P., Ho, F.K., and Lees, J.S. (2025). Cardiovascular\u2013kidney\u2013metabolic syndrome and mortality in a prospective UK cohort study. Eur. J. Prev. Cardiol., zwaf514.","DOI":"10.1093\/eurjpc\/zwaf514"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_74","unstructured":"(2026, June 23). STRING Functional Protein Association Network. Available online: https:\/\/string-db.org\/."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5840\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:10:48Z","timestamp":1783411848000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5840"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,28]]},"references-count":74,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135840"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135840","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,28]]}}}