{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:38Z","timestamp":1787028578588,"version":"build-2736575974"},"reference-count":122,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T00:00:00Z","timestamp":1769558400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China\u2014Regional Innovation Development Joint Fund Integrated Project","award":["U24A6013"],"award-info":[{"award-number":["U24A6013"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82274376"],"award-info":[{"award-number":["82274376"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key Research and Development Program Project of Guangzhou City","award":["2024B03J1287"],"award-info":[{"award-number":["2024B03J1287"]}]},{"name":"Major Science and Technology Project of Traditional Chinese Medicine in Guangzhou Area","award":["2025ZD005"],"award-info":[{"award-number":["2025ZD005"]}]},{"name":"Guangdong Provincial Key Laboratory of Informationization of Traditional Chinese Medicine","award":["2021B1212040007"],"award-info":[{"award-number":["2021B1212040007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Diabetic osteoporosis (DOP) is a metabolic bone disease characterized by abnormal bone tissue structure and reduced bone strength in patients with diabetes. Its pathogenesis is complex, involving multiple factors rather than a single cause, and has not yet been fully elucidated. Cuproptosis, a novel form of programmed cell death discovered in 2022, differs mechanistically from apoptosis, necroptosis, and ferroptosis. This process relies on the accumulation of intracellular copper ions and is closely associated with mitochondrial respiration. Studies have indicated that cuproptosis is intimately linked to glucose metabolism and bone metabolism. This review explores the role of copper homeostasis in maintaining glucose metabolism and bone quality and systematically elucidates the potential associations between cuproptosis and these processes from molecular, cellular, and pathophysiological perspectives, aiming to provide new insights and prospects for future research directions in diabetic osteoporosis.<\/jats:p>","DOI":"10.3390\/ijms27031307","type":"journal-article","created":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T15:04:46Z","timestamp":1769612686000},"page":"1307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cuproptosis and Diabetic Osteoporosis: Mechanisms and Therapeutic Prospects"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9268-5877","authenticated-orcid":false,"given":"Shih-Yu","family":"Chen","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital of Jinan University, Guangzhou 510630, China"},{"name":"School of Traditional Chinese Medicine, Jinan University, Guangzhou 510630, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanyi","family":"Chen","sequence":"additional","affiliation":[{"name":"School of the First Clinical Medical, Jinan University, Guangzhou 510630, China"},{"name":"The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou 510317, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze","family":"Gao","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Jinan University, Guangzhou 510630, China"},{"name":"School of the First Clinical Medical, Jinan University, Guangzhou 510630, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Cui","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Jinan University, Guangzhou 510630, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Zhu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Jinan University, Guangzhou 510630, China"},{"name":"School of Traditional Chinese Medicine, Jinan University, Guangzhou 510630, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00223-025-01341-5","article-title":"Fracture Risk Assessment in Metabolic Syndrome in Terms of Secondary Osteoporosis Potential. A Narrative Review","volume":"116","author":"Armutcu","year":"2025","journal-title":"Calcif. Tissue Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e41444","DOI":"10.1097\/MD.0000000000041444","article-title":"Association of type 2 diabetes with osteoporosis and fracture risk: A systematic review and meta-analysis","volume":"104","author":"Cao","year":"2025","journal-title":"Medicine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1111\/1753-0407.12962","article-title":"Management of fracture risk in patients with diabetes-Chinese Expert Consensus","volume":"11","author":"Liu","year":"2019","journal-title":"J. Diabetes"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"797s","DOI":"10.1093\/ajcn\/63.5.797","article-title":"Copper biochemistry and molecular biology","volume":"63","author":"Linder","year":"1996","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"110995","DOI":"10.1016\/j.jinorgbio.2020.110995","article-title":"Ditopic binuclear copper(II) complexes for DNA cleavage","volume":"205","author":"Mosquera","year":"2020","journal-title":"J. Inorg. Biochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1126\/science.abf0529","article-title":"Copper induces cell death by targeting lipoylated TCA cycle proteins","volume":"375","author":"Tsvetkov","year":"2022","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2431142","DOI":"10.1080\/0886022X.2024.2431142","article-title":"Copper-instigated modulatory cell mortality mechanisms and progress in kidney diseases","volume":"47","author":"Ren","year":"2025","journal-title":"Ren. Fail."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zawada, A., Ratajczak, A.E., Rychter, A.M., Szymczak-Tomczak, A., Dobrowolska, A., and Krela-Ka\u2019zmierczak, I. (2022). Treatment of Diabetes and Osteoporosis-A Reciprocal Risk?. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092191"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Liu, J., Gao, Z., and Liu, X. (2024). Mitochondrial dysfunction and therapeutic perspectives in osteoporosis. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1325317"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1007\/s00335-024-10049-0","article-title":"Revealing the key role of cuproptosis in osteoporosis via the bioinformatic analysis and experimental validation of cuproptosis-related genes","volume":"35","author":"Chen","year":"2024","journal-title":"Mamm. Genome"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.ncrna.2024.03.002","article-title":"Role of extracellular vesicles associated with microRNAs and their interplay with cuproptosis in osteoporosis","volume":"9","author":"Sun","year":"2024","journal-title":"Non-Coding RNA Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jns.2011.09.007","article-title":"New novel mutation of the ATP7B gene in a family with Wilson disease","volume":"313","author":"Lee","year":"2012","journal-title":"J. Neurol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1301\/nr.2007.jul.335\u2013340","article-title":"Steap proteins: Implications for iron and copper metabolism","volume":"65","author":"Knutson","year":"2007","journal-title":"Nutr. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1016\/j.febslet.2008.05.010","article-title":"Dcytb (Cybrd1) functions as both a ferric and a cupric reductase in vitro","volume":"582","author":"Wyman","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"jcs240523","DOI":"10.1242\/jcs.240523","article-title":"Dynamic and cell-specific transport networks for intracellular copper ions","volume":"134","author":"Lutsenko","year":"2021","journal-title":"J. Cell Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"R877","DOI":"10.1016\/j.cub.2011.09.040","article-title":"Copper: An essential metal in biology","volume":"21","author":"Festa","year":"2011","journal-title":"Curr. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/nrneurol.2010.180","article-title":"ATP7A-related copper transport diseases-emerging concepts and future trends","volume":"7","author":"Kaler","year":"2011","journal-title":"Nat. Rev. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1073\/pnas.0336230100","article-title":"Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase","volume":"100","author":"Hamza","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1146\/annurev-biochem-030409-143539","article-title":"Copper metallochaperones","volume":"79","author":"Robinson","year":"2010","journal-title":"Annu. Rev. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e2304522","DOI":"10.1002\/adhm.202304522","article-title":"Mitochondrial-Targeted Copper Delivery for Cuproptosis-Based Synergistic Cancer Therapy","volume":"13","author":"Deng","year":"2024","journal-title":"Adv. Healthc. Mater."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12964-020-00548-3","article-title":"Copper induce zebrafish retinal developmental defects via triggering stresses and apoptosis","volume":"18","author":"Zhao","year":"2020","journal-title":"Cell Commun. Signal"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2212267","DOI":"10.1002\/adma.202212267","article-title":"Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with \u03b1PD-L1 for Enhanced Cancer Immunotherapy","volume":"35","author":"Guo","year":"2023","journal-title":"Adv. Mater."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9607","DOI":"10.1039\/D2TB01639G","article-title":"ROS generation strategy based on biomimetic nanosheets by self-assembly of nanozymes","volume":"10","author":"Ling","year":"2022","journal-title":"J. Mater. Chem. B"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Luo, X., Xie, D., Wu, T., Xu, W., Meng, Q., Cao, K., and Hu, J. (2022). Evaluation of the protective roles of alpha-lipoic acid supplementation on nanomaterial-induced toxicity: A meta-analysis of in vitro and in vivo studies. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.991524"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"H2181","DOI":"10.1152\/ajpheart.00554.2011","article-title":"Oxidative stress and heart failure","volume":"301","author":"Tsutsui","year":"2011","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e01259","DOI":"10.1002\/smll.202501259","article-title":"Oligocopper-Loaded Lipoic Acid Nanoparticles Promote Mitochondrial Protein Lipoylation for Augmented Cuproptosis Therapy","volume":"21","author":"Chen","year":"2025","journal-title":"Small"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1038\/s41392-022-01014-x","article-title":"Cuproptosis: Lipoylated TCA cycle proteins-mediated novel cell death pathway","volume":"7","author":"Li","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1038\/s41580-024-00703-5","article-title":"The cell biology of ferroptosis","volume":"25","author":"Dixon","year":"2024","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1146\/annurev-pathmechdis-051222-115023","article-title":"Apoptosis in Cancer Biology and Therapy","volume":"20","author":"Moyer","year":"2025","journal-title":"Annu. Rev. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s41392-021-00507-5","article-title":"Pyroptosis: Mechanisms and diseases","volume":"6","author":"Yu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_31","first-page":"7","article-title":"Harnessing copper: Innovative ap-proaches to combat neurodegenerative diseases and cancer (Review)","volume":"57","author":"Duan","year":"2026","journal-title":"Int. J. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s12943-023-01732-y","article-title":"Cuproptosis: Mechanisms and links with cancers","volume":"22","author":"Xie","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Genchi, G., Catalano, A., Carocci, A., Sinicropi, M.S., and Lauria, G. (2025). Copper, Cuproptosis, and Neurodegenerative Diseases. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26189173"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, Y., and Wang, X. (Trends Endocrinol Metab, 2025). A metabolic perspective on cuproptosis, Trends Endocrinol Metab, in press.","DOI":"10.1016\/j.tem.2025.06.007"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Bernhardt, A., Bacova, J., Gbureck, U., and Gelinsky, M. (2021). Influence of Cu2+ on Osteoclast Formation and Activity In Vitro. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22052451"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"117817","DOI":"10.1016\/j.biopha.2025.117817","article-title":"Mechanism and therapeutic potential of hippo signaling pathway in type 2 diabetes and its complications","volume":"183","author":"Zhao","year":"2025","journal-title":"Biomed. Pharmacother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1002\/iub.1613","article-title":"The role of insufficient copper in lipid synthesis and fatty-liver disease","volume":"69","author":"Morrell","year":"2017","journal-title":"IUBMB Life"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1038\/ajg.2010.170","article-title":"A role for low hepatic copper concentrations in nonalcoholic Fatty liver disease","volume":"105","author":"Aigner","year":"2010","journal-title":"Am. J. Gastroenterol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1007\/s10534-022-00419-z","article-title":"Associations between whole blood trace elements concentrations and HbA1c levels in patients with type 2 diabetes","volume":"35","author":"Luan","year":"2022","journal-title":"Biometals"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"6643","DOI":"10.2174\/0929867326666190902122155","article-title":"The Role of Zinc and Copper in Insulin Resistance and Diabetes Mellitus","volume":"27","author":"Dadar","year":"2020","journal-title":"Curr. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"86","DOI":"10.4103\/1735-5362.329929","article-title":"Determination of plasma and erythrocyte levels of copper, magnesium and zinc by atomic absorption spectrometry in type-2 diabetes mellitus patients with metabolic syndrome","volume":"17","author":"Omidian","year":"2022","journal-title":"Res. Pharm. Sci."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cui, Z., Chen, H., Lu, W., Wang, P., Zhou, Z., Zhang, N., Wang, Z., Lin, T., Song, Y., and Liu, L. (2022). The Association Between Plasma Copper Concentration and Prevalence of Diabetes in Chinese Adults With Hypertension. Front. Public Health, 10.","DOI":"10.3389\/fpubh.2022.888219"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1113\/JP280572","article-title":"Regulation of glycolysis by the hypoxia-inducible factor (HIF): Implications for cellular physiology","volume":"599","author":"Kierans","year":"2021","journal-title":"J. Physiol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Rondanelli, M., Faliva, M.A., Infantino, V., Gasparri, C., Iannello, G., Perna, S., Riva, A., Petrangolini, G., Tartara, A., and Peroni, G. (2021). Copper as Dietary Supplement for Bone Metabolism: A Review. Nutrients, 13.","DOI":"10.3390\/nu13072246"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Ciosek, Z., Kot, K., and Rotter, I. (2023). Iron, Zinc, Copper, Cadmium, Mercury, and Bone Tissue. Int. J. Environ. Res. Public Health, 20.","DOI":"10.3390\/ijerph20032197"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1002\/biof.2052","article-title":"SP1\/CTR1-mediated oxidative stress-induced cuproptosis in intervertebral disc degeneration","volume":"50","author":"Chen","year":"2024","journal-title":"Biofactors"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1152\/physrev.00011.2024","article-title":"Mammalian copper homeostasis: Physiological roles and molecular mechanisms","volume":"105","author":"Lutsenko","year":"2025","journal-title":"Physiol. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1186\/s13018-024-05280-z","article-title":"Exploration and breakthrough in the mode of intervertebral disc cell death may lead to significant advances in treatments for intervertebral disc degeneration","volume":"19","author":"Chen","year":"2024","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1515\/cclm-2012-0868","article-title":"Trace elements and bone health","volume":"51","author":"Nemcikova","year":"2013","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Li, M., Deng, F., Qiao, L., Wen, X., and Han, J. (2024). The Critical Role of Trace Elements in Bone Health. Nutrients, 16.","DOI":"10.3390\/nu16223867"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3556","DOI":"10.1002\/jbm.a.35032","article-title":"Effects of Cu-doped 45S5 bioactive glass on the lipid peroxidation-associated growth of human osteoblast-like cells in vitro","volume":"102","author":"Milkovic","year":"2014","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_52","first-page":"34","article-title":"Serum copper levels are associated with bone mineral density and total fracture","volume":"14","author":"Qu","year":"2018","journal-title":"J. Orthop. Transl."},{"key":"ref_53","first-page":"19250","article-title":"Correlation between bone mineral density and serum trace element contents of elderly males in Beijing urban area","volume":"8","author":"Wang","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2368","DOI":"10.1002\/jbmr.1981","article-title":"Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading","volume":"28","author":"Morikawa","year":"2013","journal-title":"J. Bone Miner. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1002\/jbmr.489","article-title":"Cytoplasmic superoxide causes bone fragility owing to low-turnover osteoporosis and impaired collagen cross-linking","volume":"26","author":"Nojiri","year":"2011","journal-title":"J. Bone Miner. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1111\/cpr.12083","article-title":"Inhibition of osteogenic differentiation of mesenchymal stem cells by copper supplementation","volume":"47","author":"Li","year":"2014","journal-title":"Cell Prolif."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1177\/1535370216648805","article-title":"Copper, iron, and selenium dietary deficiencies negatively impact skeletal integrity: A review","volume":"241","author":"Medeiros","year":"2016","journal-title":"Exp. Biol. Med."},{"key":"ref_58","first-page":"18","article-title":"Copper, magnesium, zinc and calcium status in osteopenic and osteoporotic post-menopausal women","volume":"12","author":"Ebrahimi","year":"2015","journal-title":"Clin. Cases Min. Bone Metab."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Li, D., Gao, Z., Li, Q., Liu, X., and Liu, H. (2023). Cuproptosis-a potential target for the treatment of osteoporosis. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1135181"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1007\/s00198-019-05122-3","article-title":"The association between type 2 diabetes mellitus, hip fracture, and post-hip fracture mortality: A multi-state cohort analysis","volume":"30","author":"Reyes","year":"2019","journal-title":"Osteoporos. Int."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"115457","DOI":"10.1016\/j.bone.2020.115457","article-title":"The risk of hip and non-vertebral fractures in type 1 and type 2 diabetes: A systematic review and meta-analysis update","volume":"137","author":"Vilaca","year":"2020","journal-title":"Bone"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jocd.2019.04.004","article-title":"Osteoporosis and Osteopenia Among Patients With Type 2 Diabetes Aged \u2265 50: Role of Sex and Clinical Characteristics","volume":"23","author":"Xu","year":"2020","journal-title":"J. Clin. Densitom."},{"key":"ref_63","first-page":"281","article-title":"Acupuncture for Osteoporosis: A Review of Its Clinical and Preclinical Studies","volume":"15","author":"Tian","year":"2022","journal-title":"Innov. Acupunct. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"114834","DOI":"10.1016\/j.biopha.2023.114834","article-title":"Oxidative stress: A common pathological state in a high-risk population for osteoporosis","volume":"163","author":"Zhang","year":"2023","journal-title":"Biomed. Pharmacother."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1007\/s40200-021-00733-2","article-title":"Review of osteoporotic fracture research in Endocrinology and Metabolism Research Institute; where we started and where to go","volume":"23","author":"Fahimfar","year":"2024","journal-title":"J. Diabetes Metab. Disord."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"101172","DOI":"10.1016\/j.redox.2019.101172","article-title":"Interactions between plasma copper concentrations and SOD1 gene polymorphism for impaired glucose regulation and type 2 diabetes","volume":"24","author":"Yin","year":"2019","journal-title":"Redox Biol."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Zhou, J., Liu, C., Francis, M., Sun, Y., Ryu, M.S., Grider, A., and Ye, K. (2020). The Causal Effects of Blood Iron and Copper on Lipid Metabolism Diseases: Evidence from Phenome-Wide Mendelian Randomization Study. Nutrients, 12.","DOI":"10.1101\/2020.09.17.20196956"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"143753","DOI":"10.1016\/j.scitotenv.2020.143753","article-title":"Activation of the ROS\/HO-1\/NQO1 signaling pathway contributes to the copper-induced oxidative stress and autophagy in duck renal tubular epithelial cells","volume":"757","author":"Fang","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2922","DOI":"10.1016\/j.clnu.2018.12.032","article-title":"Association between plasma concentration of copper and gestational diabetes mellitus","volume":"38","author":"Li","year":"2019","journal-title":"Clin. Nutr."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"110236","DOI":"10.1016\/j.ecoenv.2020.110236","article-title":"Copper sulfate-induced endoplasmic reticulum stress promotes hepatic apoptosis by activating CHOP, JNK and caspase-12 signaling pathways","volume":"191","author":"Wu","year":"2020","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_71","first-page":"1359164","article-title":"Copper Induces Oxidative Stress and Apoptosis in the Mouse Liver","volume":"2020","author":"Liu","year":"2020","journal-title":"Oxidative Med. Cell Longev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.aquatox.2010.04.005","article-title":"Apoptosis and necroptosis are induced in rainbow trout cell lines exposed to cadmium","volume":"99","author":"Krumschnabel","year":"2010","journal-title":"Aquat. Toxicol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.4049\/jimmunol.1700712","article-title":"Copper Regulates the Canonical NLRP3 Inflam-masome","volume":"200","author":"Deigendesch","year":"2018","journal-title":"J. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ecoenv.2019.02.069","article-title":"Inhibition of Caspase-1-dependent pyroptosis attenuates copper-induced apoptosis in chicken hepatocytes","volume":"174","author":"Liao","year":"2019","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"7916","DOI":"10.1039\/C8SC04041A","article-title":"Cu2+ selective chelators relieve copper-induced oxidative stress in vivo","volume":"9","author":"Rakshit","year":"2018","journal-title":"Chem. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.freeradbiomed.2017.11.015","article-title":"Potentiation of glutathione loss and nerve cell death by the transition metals iron and copper: Implications for age-related neurodegenerative diseases","volume":"115","author":"Maher","year":"2018","journal-title":"Free Radic. Biol. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"111741","DOI":"10.1016\/j.msec.2020.111741","article-title":"Copper-containing bioactive glasses and glass-ceramics: From tissue regeneration to cancer therapeutic strategies","volume":"121","author":"Kargozar","year":"2021","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"103613","DOI":"10.1016\/j.etap.2021.103613","article-title":"The role of TGF-\u03b21\/Smad3 signaling pathway and oxida-tive stress in the inhibition of osteoblast mineralization by copper chloride","volume":"84","author":"Qi","year":"2021","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1089\/scd.2013.0486","article-title":"Dimethyloxaloylglycine increases the bone healing capacity of adipose-derived stem cells by promoting osteogenic differentiation and angiogenic potential","volume":"23","author":"Ding","year":"2014","journal-title":"Stem Cells Dev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"116954","DOI":"10.1016\/j.biopha.2024.116954","article-title":"Unraveling the molecular and immunological landscape: Exploring signaling pathways in osteoporosis","volume":"177","author":"Amroodi","year":"2024","journal-title":"Biomed. Pharmacother."},{"key":"ref_81","first-page":"235","article-title":"Osteoporosis and diabetes","volume":"56","author":"Dominguez","year":"2004","journal-title":"Reumatismo"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.jtemb.2019.05.003","article-title":"Heavy metal toxicity: An update of chelating therapeutic strategies","volume":"54","author":"Kim","year":"2019","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"e2300468","DOI":"10.1002\/mnfr.202300468","article-title":"Copper and Diabetes: Current Research and Prospect","volume":"67","author":"Chang","year":"2023","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Gembillo, G., Labbozzetta, V., Giuffrida, A.E., Peritore, L., Calabrese, V., Spinella, C., Stancanelli, R., Spallino, E., Visconti, L., and Santoro, D. (2022). Potential Role of Copper in Diabetes and Diabetic Kidney Disease. Metabolites, 13.","DOI":"10.3390\/metabo13010017"},{"key":"ref_85","first-page":"125","article-title":"The impact of copper on bone metabolism","volume":"47","author":"Zhang","year":"2024","journal-title":"J. Orthop. Transl."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1039\/C9MT00148D","article-title":"Obesity is associated with copper elevation in serum and tissues","volume":"11","author":"Yang","year":"2019","journal-title":"Metallomics"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1016\/j.freeradbiomed.2012.03.017","article-title":"The oncology drug elesclomol selectively transports copper to the mitochondria to induce oxidative stress in cancer cells","volume":"52","author":"Nagai","year":"2012","journal-title":"Free Radic. Biol. Med."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Modica-Napolitano, J.S., Bharath, L.P., Hanlon, A.J., and Hurley, L.D. (2019). The Anticancer Agent Elesclomol Has Direct Effects on Mitochondrial Bioenergetic Function in Isolated Mammalian Mitochondria. Biomolecules, 9.","DOI":"10.3390\/biom9080298"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1158\/1535-7163.MCT-08-0298","article-title":"Elesclomol induces cancer cell apoptosis through oxidative stress","volume":"7","author":"Kirshner","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1126\/science.aaz8899","article-title":"Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice","volume":"368","author":"Guthrie","year":"2020","journal-title":"Science"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1186\/s13046-022-02485-0","article-title":"Elesclomol: A copper ionophore targeting mitochon-drial metabolism for cancer therapy","volume":"41","author":"Zheng","year":"2022","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3860","DOI":"10.1158\/1078-0432.CCR-15-1798","article-title":"Disulfiram when Combined with Copper Enhances the Therapeutic Effects of Temozolomide for the Treatment of Glioblastoma","volume":"22","author":"Lun","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3527","DOI":"10.1002\/1878-0261.13079","article-title":"Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A","volume":"15","author":"Gao","year":"2021","journal-title":"Mol. Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e18655","DOI":"10.1016\/j.heliyon.2023.e18655","article-title":"FDX1 inhibits thyroid cancer malignant progression by inducing cuprotosis","volume":"9","author":"Chen","year":"2023","journal-title":"Heliyon"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1186\/s13046-021-02031-4","article-title":"Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth","volume":"40","author":"Buccarelli","year":"2021","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Harrington, B.S., Ozaki, M.K., Caminear, M.W., Hernandez, L.F., Jordan, E., Kalinowski, N.J., Goldlust, I.S., Guha, R., Ferrer, M., and Thomas, C. (2020). Drugs Targeting Tumor-Initiating Cells Prolong Survival in a Post-Surgery, Post-Chemotherapy Ovarian Cancer Relapse Model. Cancers, 12.","DOI":"10.3390\/cancers12061645"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41568-021-00417-2","article-title":"Connecting copper and cancer: From transition metal signalling to metalloplasia","volume":"22","author":"Ge","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e23145","DOI":"10.1096\/fj.202300980R","article-title":"Cuproptosis enhances docetaxel chemosensitivity by inhibiting autophagy via the DLAT\/mTOR pathway in prostate cancer","volume":"37","author":"Wen","year":"2023","journal-title":"FASEB J."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1097\/BS9.0000000000000117","article-title":"Disulfiram, an aldehyde dehydrogenase inhibitor, works as a potent drug against sepsis and cancer via NETosis, pyroptosis, apoptosis, ferroptosis, and cuproptosis","volume":"4","author":"Nie","year":"2022","journal-title":"Blood Sci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/s41392-022-01229-y","article-title":"Copper homeostasis and cuproptosis in health and disease","volume":"7","author":"Chen","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"121880","DOI":"10.1016\/j.biomaterials.2022.121880","article-title":"Disulfiram loaded calcium phosphate nanoparticles for enhanced cancer immunotherapy","volume":"291","author":"Li","year":"2022","journal-title":"Biomaterials"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"3996","DOI":"10.1158\/0008-5472.CAN-09-3752","article-title":"Disulfiram treatment facilitates phosphoinositide 3-kinase inhibition in human breast cancer cells in vitro and in vivo","volume":"70","author":"Zhang","year":"2010","journal-title":"Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1186\/s12935-022-02661-4","article-title":"DSF\/Cu induces antitumor effect against diffuse large B-cell lymphoma through suppressing NF-\u03baB\/BCL6 pathways","volume":"22","author":"Zhu","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.jconrel.2023.02.023","article-title":"Overcoming drug resistance with a docetaxel and disulfiram loaded pH-sensitive nanoparticle","volume":"356","author":"Swetha","year":"2023","journal-title":"J. Control. Release"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Kang, X., Jadhav, S., Annaji, M., Huang, C.H., Amin, R., Shen, J., Ashby, C.R., Tiwari, A.K., Babu, R.J., and Chen, P. (2023). Advancing Cancer Therapy with Copper\/Disulfiram Nanomedicines and Drug Delivery Systems. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15061567"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1038\/s41418-020-0550-z","article-title":"Chemical activation of SAT1 corrects diet-induced metabolic syndrome","volume":"27","author":"Castoldi","year":"2020","journal-title":"Cell Death Differ."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Ramli, F.F., Hashim, S.A.S., Raman, B., Mahmod, M., and Kamisah, Y. (2022). Role of Trientine in Hypertrophic Cardiomyopathy: A Review of Mechanistic Aspects. Pharmaceuticals, 15.","DOI":"10.3390\/ph15091145"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Baldari, S., Di Rocco, G., and Toietta, G. (2020). Current Biomedical Use of Copper Chelation Therapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21031069"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1002\/biof.1837","article-title":"Copper chelation therapy inhibits renal fibrosis by modulating copper transport proteins","volume":"48","author":"Saifi","year":"2022","journal-title":"Biofactors"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1002\/jcp.30717","article-title":"Disulfiram prevents collagen crosslinking and inhibits renal fibrosis by inhibiting lysyl oxidase enzymes","volume":"237","author":"Saifi","year":"2022","journal-title":"J. Cell Physiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ctrv.2008.07.004","article-title":"Elevated copper and oxidative stress in cancer cells as a target for cancer treatment","volume":"35","author":"Gupte","year":"2009","journal-title":"Cancer Treat. Rev."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"14055","DOI":"10.1038\/s41598-019-50494-5","article-title":"High-affinity Cu(I) chelator PSP-2 as potential anti-angiogenic agent","volume":"9","author":"Heuberger","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1002\/ijc.1537","article-title":"The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells","volume":"94","author":"Yoshii","year":"2001","journal-title":"Int. J. Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/1475-2840-13-100","article-title":"Diabetic cardiomyopathy is associated with defective myocellular copper regulation and both defects are rectified by divalent copper chelation","volume":"13","author":"Zhang","year":"2014","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1039\/c9mt00223e","article-title":"Restoration of myocellular copper-trafficking proteins and mitochondrial copper enzymes repairs cardiac function in rats with diabetes-evoked heart failure","volume":"12","author":"Zhang","year":"2020","journal-title":"Metallomics"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/s41574-019-0242-2","article-title":"Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus","volume":"15","author":"Foretz","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.jdiacomp.2019.04.005","article-title":"The effect of EDTA-based chelation on patients with diabetes and peripheral artery disease in the Trial to Assess Chelation Therapy (TACT)","volume":"33","author":"Ujueta","year":"2019","journal-title":"J. Diabetes Complicat."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s10534-011-9467-9","article-title":"Metal chelation therapy in rheumath-oid arthritis: A case report. Successful management of rheumathoid arthritis by metal chelation therapy","volume":"24","author":"Bamonti","year":"2011","journal-title":"Biometals"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/0006-2952(78)90378-7","article-title":"Inhibition of the denaturation of human gamma globulin by a mixture of D-penicillamine disulfide and copper. A possible mechanism of action of D-penicillamine in rheumatoid arthritis","volume":"27","author":"Gerber","year":"1978","journal-title":"Biochem. Pharmacol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1080\/14740338.2021.1956460","article-title":"Safety profile of D-penicillamine: A comprehensive pharmacovigilance analysis by FDA adverse event reporting system","volume":"20","author":"Kumar","year":"2021","journal-title":"Expert Opin. Drug Saf."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"e26759","DOI":"10.1016\/j.heliyon.2024.e26759","article-title":"Identification and immunological role of cuproptosis in osteoporosis","volume":"10","author":"Chen","year":"2024","journal-title":"Heliyon"},{"key":"ref_122","doi-asserted-by":"crossref","unstructured":"Wu, H., Wu, J., and Wen, G. (2025). Cuproptosis related genes in immune infiltration and treatment of osteoporosis by bioinformatic analysis and machine learning methods. Front. Physiol., 16.","DOI":"10.3389\/fphys.2025.1605473"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1307\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,30]],"date-time":"2026-01-30T05:11:01Z","timestamp":1769749861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/3\/1307"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,28]]},"references-count":122,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27031307"],"URL":"https:\/\/doi.org\/10.3390\/ijms27031307","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,28]]}}}