{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T14:03:55Z","timestamp":1793109835867,"version":"4.5.0"},"reference-count":54,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100009162","name":"Universidade Estadual De Londrina","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100009162","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Copper-based metallodrugs are promising anticancer agents, but their toxicity limits clinical translation. This study evaluated the toxicological and molecular effects of PEGylated Fluopsin C (PEG-FlpC) in in vitro human non-small-cell lung carcinoma (NCI-H460) cells cultured as 2D monolayer and 3D spheroids. Cells were exposed to PEG-FlpC at its IC\n                    <jats:sub>50<\/jats:sub>\n                    (1.0\u00a0\u00b5M) for 24\u00a0h. Flow cytometry revealed G\u2081-phase arrest and non-apoptotic cell death. PEG-FlpC markedly suppressed spheroid growth, with 2\u2009\u00d7\u2009IC\n                    <jats:sub>50<\/jats:sub>\n                    -treated spheroids growing only 58.1% compared to 131.6% in the control. Ultrastructural analyses showed mitochondrial clustering and swelling, ER dilation, and cytoplasmic vacuolization. Gene profiling demonstrated downregulation of\n                    <jats:italic>TP53<\/jats:italic>\n                    and\n                    <jats:italic>BECN1<\/jats:italic>\n                    , with upregulation of\n                    <jats:italic>TP73<\/jats:italic>\n                    and\n                    <jats:italic>SQSTM1<\/jats:italic>\n                    , consistent with autophagy blockade and stress activation. PEG-FlpC modulated ferroptosis-related (\n                    <jats:italic>GPX4<\/jats:italic>\n                    ,\n                    <jats:italic>SLC7A11<\/jats:italic>\n                    , and\n                    <jats:italic>TFRC<\/jats:italic>\n                    ) and cuproptosis-related (\n                    <jats:italic>ATP7B<\/jats:italic>\n                    ,\n                    <jats:italic>MTF1<\/jats:italic>\n                    ,\n                    <jats:italic>DLAT<\/jats:italic>\n                    , and\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    ) genes. Pharmacological inhibition confirmed a predominantly copper-mediated mechanism, as TTM (10\u00a0\u00b5M) restored 77.7% of metabolic activity. Combined inhibition with TTM and Fer-1 (1\u00a0\u00b5M) further increased viability to 89.4%, indicating that PEG-FlpC induces non-apoptotic regulated cell death through an interconnected cuproptosis\u2013ferroptosis mechanism associated with mitochondrial dysfunction.\n                  <\/jats:p>","DOI":"10.1007\/s00204-026-04315-0","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:27:52Z","timestamp":1772152072000},"page":"1981-1994","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PEGylated liposomal fluopsin C triggers cuproptosis and ferroptosis pathways and suppresses 3D tumor spheroid growth in NCI-H460 cells"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0360-2889","authenticated-orcid":false,"given":"Luan Vitor Alves","family":"de Lima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matheus Felipe","family":"da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liana Martins","family":"de Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Claudia Terkelli","family":"de Assis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella Cristina Oliveira","family":"Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaura Maria","family":"Fuzinatto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone Cristine","family":"Semprebon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renan Vin\u00edcius","family":"de Oliveira Nocetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Lazarin-Bidoia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celso Vataru","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Felicidade","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra Regina","family":"Lepri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phelipe Oliveira","family":"Favaron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mickely Liuti","family":"Dealis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Fernando","family":"Cabe\u00e7a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galdino Andrade","family":"Filho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rio S\u00e9rgio","family":"Mantovani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"issue":"Supplement 1","key":"4315_CR1","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1182\/blood-2021-148248","volume":"138","author":"H Akiyama","year":"2021","unstructured":"Akiyama H, Zhao R, Rahhal A et al (2021) Therapeutic targeting of ferroptosis pathway in combination with mitochondrial oxidative stress induction in acute myeloid leukemia. Blood 138(Supplement 1):1162\u20131162. https:\/\/doi.org\/10.1182\/blood-2021-148248","journal-title":"Blood"},{"issue":"19","key":"4315_CR3","doi-asserted-by":"publisher","first-page":"4562","DOI":"10.3390\/cancers14194562","volume":"14","author":"A Ashrafi","year":"2022","unstructured":"Ashrafi A, Akter Z, Modareszadeh P et al (2022) Current landscape of therapeutic resistance in lung cancer and promising strategies to overcome resistance. Cancers 14(19):4562. https:\/\/doi.org\/10.3390\/cancers14194562","journal-title":"Cancers"},{"issue":"13","key":"4315_CR4","doi-asserted-by":"publisher","first-page":"3497","DOI":"10.1073\/pnas.1702663114","volume":"14","author":"C Bouvard","year":"2017","unstructured":"Bouvard C, Lim SM, Ludka J et al (2017) Small molecule selectively suppresses MYC transcription in cancer cells. Proc Natl Acad Sci (PNAS) 14(13):3497\u20133502. https:\/\/doi.org\/10.1073\/pnas.1702663114","journal-title":"Proc Natl Acad Sci (PNAS)"},{"issue":"7","key":"4315_CR5","doi-asserted-by":"publisher","first-page":"3711","DOI":"10.3390\/ijms22073711","volume":"22","author":"S-Y Chen","year":"2021","unstructured":"Chen S-Y, Chang Y-L, Liu S-T et al (2021) Differential cytotoxicity mechanisms of copper complexed with Disulfiram in oral cancer cells. Int J Mol Sci 22(7):3711. https:\/\/doi.org\/10.3390\/ijms22073711","journal-title":"Int J Mol Sci"},{"issue":"3","key":"4315_CR6","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1385\/mb:26:3:249","volume":"26","author":"AR Collins","year":"2004","unstructured":"Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26(3):249\u2013261. https:\/\/doi.org\/10.1385\/mb:26:3:249","journal-title":"Mol Biotechnol"},{"key":"4315_CR7","doi-asserted-by":"publisher","first-page":"122033","DOI":"10.1016\/j.lfs.2023.122033","volume":"330","author":"MF da Silva","year":"2023","unstructured":"da Silva MF, Lima LVA, de Oliveira LM et al (2023) Regulation of cytokinesis and necroptosis pathways by Diosgenin inhibits the proliferation of NCI-H460 lung cancer cells. Life Sci 330:122033. https:\/\/doi.org\/10.1016\/j.lfs.2023.122033","journal-title":"Life Sci"},{"issue":"21","key":"4315_CR2","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1080\/15287394.2022.2108950","volume":"85","author":"LV de Alves","year":"2022","unstructured":"de Alves LV, da Silva MF, Concato VM et al (2022) DNA damage and reticular stress in cytotoxicity and oncotic cell death of MCF-7 cells treated with Fluopsin C. J Toxicol Environ Health A 85(21):896\u2013911. https:\/\/doi.org\/10.1080\/15287394.2022.2108950","journal-title":"J Toxicol Environ Health A"},{"key":"4315_CR8","doi-asserted-by":"publisher","unstructured":"Dealis Gomes ML, Afonso L, Basso KR et al (2025) Liposomal fluopsin C: physicochemical properties, cytotoxicity, and antibacterial activity in vitro and over in vivo MDR Klebsiella pneumoniae bacteremia model. Antibiotics 14(9):948. https:\/\/doi.org\/10.3390\/antibiotics14090948","DOI":"10.3390\/antibiotics14090948"},{"issue":"5","key":"4315_CR9","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","volume":"149","author":"SJ Dixon","year":"2012","unstructured":"Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an Iron-Dependent form of nonapoptotic cell death. Cell 149(5):1060\u20131072. https:\/\/doi.org\/10.1016\/j.cell.2012.03.042","journal-title":"Cell"},{"issue":"7784","key":"4315_CR10","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41586-019-1707-0","volume":"575","author":"S Doll","year":"2019","unstructured":"Doll S, Freitas FP, Shah R et al (2019) FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575(7784):693\u2013698. https:\/\/doi.org\/10.1038\/s41586-019-1707-0","journal-title":"Nature"},{"key":"4315_CR11","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.ejca.2017.06.023","volume":"83","author":"MJ Duffy","year":"2017","unstructured":"Duffy MJ, Synnott NC, Crown J (2017) Mutant p53 as a target for cancer treatment. Eur J Cancer 83:258\u2013265. https:\/\/doi.org\/10.1016\/j.ejca.2017.06.023","journal-title":"Eur J Cancer"},{"issue":"3","key":"4315_CR12","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1038\/nprot.2008.226","volume":"4","author":"J Friedrich","year":"2009","unstructured":"Friedrich J, Seidel C, Ebner R, Kunz-Schughart LA (2009) Spheroid-based drug screen: considerations and practical approach. Nat Protoc 4(3):309\u2013324. https:\/\/doi.org\/10.1038\/nprot.2008.226","journal-title":"Nat Protoc"},{"issue":"7","key":"4315_CR13","doi-asserted-by":"publisher","first-page":"6615","DOI":"10.3390\/ijms24076615","volume":"24","author":"MD Fulton","year":"2023","unstructured":"Fulton MD, Najahi-Missaoui W (2023) Liposomes in cancer therapy: how did we start and where are we now. Int J Mol Sci 24(7):6615. https:\/\/doi.org\/10.3390\/ijms24076615","journal-title":"Int J Mol Sci"},{"issue":"12","key":"4315_CR15","doi-asserted-by":"publisher","first-page":"3527","DOI":"10.1002\/1878-0261.13079","volume":"15","author":"W Gao","year":"2021","unstructured":"Gao W, Huang Z, Duan J et al (2021) Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A. Mol Oncol 15(12):3527\u20133544. https:\/\/doi.org\/10.1002\/1878-0261.13079","journal-title":"Mol Oncol"},{"issue":"3","key":"4315_CR14","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1007\/s11596-023-2755-0","volume":"43","author":"F Gao","year":"2023","unstructured":"Gao F, Yuan Y, Ding Y et al (2023) DLAT as a Cuproptosis promoter and a molecular target of elesclomol in hepatocellular carcinoma. Curr Med Sci 43(3):526\u2013538. https:\/\/doi.org\/10.1007\/s11596-023-2755-0","journal-title":"Curr Med Sci"},{"key":"4315_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.aanat.2017.10.002","volume":"216","author":"U Gr\u00e4sser","year":"2018","unstructured":"Gr\u00e4sser U, Bubel M, Sossong D et al (2018) Dissociation of mono-and co-culture spheroids into single cells for subsequent flow cytometric analysis. Ann Anat 216:1\u20138. https:\/\/doi.org\/10.1016\/j.aanat.2017.10.002","journal-title":"Ann Anat"},{"issue":"11","key":"4315_CR17","doi-asserted-by":"publisher","first-page":"a041079","DOI":"10.1101\/cshperspect.a041079","volume":"14","author":"DR Green","year":"2022","unstructured":"Green DR (2022) Nonapoptotic cell death pathways. Cold Spring Harb Perspect Biol 14(11):a041079. https:\/\/doi.org\/10.1101\/cshperspect.a041079","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"1","key":"4315_CR18","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/s00775-020-01841-9","volume":"26","author":"Y Gu","year":"2021","unstructured":"Gu Y, Wen H, Zhang Y et al (2021) Studies of anticancer activity in vivo and in vitro behaviors of liposomes encapsulated iridium(III) complex. J Biol Inorg Chem 26(1):109\u2013122. https:\/\/doi.org\/10.1007\/s00775-020-01841-9","journal-title":"J Biol Inorg Chem"},{"key":"4315_CR20","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.neurobiolaging.2020.05.018","volume":"98","author":"C Guo","year":"2021","unstructured":"Guo C, Zhang Y, Nie Q et al (2021) SQSTM1\/ p62 oligomerization contributes to A\u03b2-induced Inhibition of Nrf2 signaling. Neurobiol Aging 98:10\u201320. https:\/\/doi.org\/10.1016\/j.neurobiolaging.2020.05.018","journal-title":"Neurobiol Aging"},{"issue":"22","key":"4315_CR19","doi-asserted-by":"publisher","first-page":"e2212267","DOI":"10.1002\/adma.202212267","volume":"35","author":"B Guo","year":"2023","unstructured":"Guo B, Yang F, Zhang L et al (2023) Cuproptosis induced by ROS responsive nanoparticles with elesclomol and copper combined with \u03b1PD-L1 for enhanced cancer immunotherapy. Adv Mater 35(22):e2212267. https:\/\/doi.org\/10.1002\/adma.202212267","journal-title":"Adv Mater"},{"issue":"1","key":"4315_CR21","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1186\/s12935-021-01853-8","volume":"21","author":"SJ Han","year":"2021","unstructured":"Han SJ, Kwon S, Kim KS (2021) Challenges of applying multicellular tumor spheroids in preclinical phase. Cancer Cell Int 21(1):152. https:\/\/doi.org\/10.1186\/s12935-021-01853-8","journal-title":"Cancer Cell Int"},{"issue":"7","key":"4315_CR22","doi-asserted-by":"publisher","first-page":"6985","DOI":"10.1021\/acsnano.5b01324","volume":"9","author":"AE Hansen","year":"2015","unstructured":"Hansen AE, Petersen AL, Henriksen JR et al (2015) Positron emission tomography based Elucidation of the enhanced permeability and retention effect in dogs with cancer using copper-64 liposomes. ACS Nano 9(7):6985\u20136995. https:\/\/doi.org\/10.1021\/acsnano.5b01324","journal-title":"ACS Nano"},{"issue":"8","key":"4315_CR29","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1038\/aps.2013.44","volume":"34","author":"MAL-S Jian","year":"2013","unstructured":"Ma LS, Jiang CY, Cui M et al (2013) Fluopsin C induces oncosis of human breast adenocarcinoma cells. Acta Pharmacol Sin 34(8):1093\u20131100. https:\/\/doi.org\/10.1038\/aps.2013.44","journal-title":"Acta Pharmacol Sin"},{"issue":"10","key":"4315_CR23","doi-asserted-by":"publisher","first-page":"4089","DOI":"10.1039\/D4EN00455H","volume":"11","author":"M Jiang","year":"2024","unstructured":"Jiang M, Tao X, Pang Y et al (2024) Copper oxide nanoparticles induce Cuproptosis and ferroptosis through mitochondrial concatenation. Environ Sci: Nano 11(10):4089\u20134101. https:\/\/doi.org\/10.1039\/D4EN00455H","journal-title":"Environ Sci: Nano"},{"issue":"1","key":"4315_CR24","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.bbrc.2020.07.082","volume":"530","author":"N Kikuchi","year":"2020","unstructured":"Kikuchi N, Soga T, Nomura M et al (2020) Comparison of the ischemic and non-ischemic lung cancer metabolome reveals hyper activity of the TCA cycle and autophagy. Biochem Biophys Res Commun 530(1):285\u2013291. https:\/\/doi.org\/10.1016\/j.bbrc.2020.07.082","journal-title":"Biochem Biophys Res Commun"},{"issue":"5","key":"4315_CR25","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1038\/s41418-024-01279-5","volume":"31","author":"K Lai","year":"2024","unstructured":"Lai K, Wang J, Lin S et al (2024) Sensing of mitochondrial DNA by ZBP1 promotes RIPK3-mediated necroptosis and ferroptosis in response to Diquat poisoning. Cell Death Differ 31(5):635\u2013650. https:\/\/doi.org\/10.1038\/s41418-024-01279-5","journal-title":"Cell Death Differ"},{"issue":"1","key":"4315_CR26","doi-asserted-by":"publisher","first-page":"7310","DOI":"10.1038\/s41467-021-27597-7","volume":"12","author":"A Le Thomas","year":"2021","unstructured":"Le Thomas A, Ferri E, Marsters S et al (2021) Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1\u03b1. Nat Commun 12(1):7310. https:\/\/doi.org\/10.1038\/s41467-021-27597-7","journal-title":"Nat Commun"},{"issue":"12","key":"4315_CR27","doi-asserted-by":"publisher","first-page":"4323","DOI":"10.1080\/15548627.2021.1912270","volume":"17","author":"X Li","year":"2021","unstructured":"Li X, Yang K-B, Chen W et al (2021) CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression. Autophagy 17(12):4323\u20134340. https:\/\/doi.org\/10.1080\/15548627.2021.1912270","journal-title":"Autophagy"},{"key":"4315_CR28","doi-asserted-by":"publisher","first-page":"116115","DOI":"10.1016\/j.biopha.2023.116115","volume":"171","author":"N Liu","year":"2024","unstructured":"Liu N, Chen M (2024) Crosstalk between ferroptosis and cuproptosis: from mechanism to potential clinical application. Biomed Pharmacother 171:116115. https:\/\/doi.org\/10.1016\/j.biopha.2023.116115","journal-title":"Biomed Pharmacother"},{"issue":"3","key":"4315_CR30","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1016\/j.bbrc.2020.04.127","volume":"527","author":"S Miyake","year":"2020","unstructured":"Miyake S, Murai S, Kakuta S et al (2020) Identification of the hallmarks of necroptosis and ferroptosis by transmission electron microscopy. Biochem Biophys Res Commun 527(3):839\u2013844. https:\/\/doi.org\/10.1016\/j.bbrc.2020.04.127","journal-title":"Biochem Biophys Res Commun"},{"key":"4315_CR31","doi-asserted-by":"publisher","first-page":"2431","DOI":"10.3389\/fmicb.2019.02431","volume":"10","author":"MOP Navarro","year":"2019","unstructured":"Navarro MOP, Simionato AS, P\u00e9rez JCB et al (2019) Fluopsin C for treating multidrug-resistant infections: in vitro activity against clinically important strains and in vivo efficacy against Carbapenemase-Producing Klebsiella pneumoniae. Front Microbiol 10:2431. https:\/\/doi.org\/10.3389\/fmicb.2019.02431","journal-title":"Front Microbiol"},{"issue":"5","key":"4315_CR32","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1016\/j.celrep.2019.04.005","volume":"27","author":"M Ni","year":"2019","unstructured":"Ni M, Solmonson A, Pan C et al (2019) Functional assessment of Lipoyltransferase-1 deficiency in Cells, Mice, and humans. Cell Rep 27(5):1376\u20131386e6. https:\/\/doi.org\/10.1016\/j.celrep.2019.04.005","journal-title":"Cell Rep"},{"issue":"33","key":"4315_CR33","doi-asserted-by":"publisher","first-page":"21162","DOI":"10.1021\/acsomega.0c02879","volume":"5","author":"M Niora","year":"2020","unstructured":"Niora M, Pedersb\u00e6k D, M\u00fcnter R et al (2020) Head-to-head comparison of the penetration efficiency of lipid-based nanoparticles into tumor spheroids. Acs Omega 5(33):21162\u201321171. https:\/\/doi.org\/10.1021\/acsomega.0c02879","journal-title":"Acs Omega"},{"issue":"1","key":"4315_CR34","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1002\/bit.26845","volume":"116","author":"AS Nunes","year":"2019","unstructured":"Nunes AS, Barros AS, Costa EC et al (2019) 3D tumor spheroids as in vitro models to mimic in vivo human solid tumors resistance to therapeutic drugs. Biotechnol Bioeng 116(1):206\u2013226. https:\/\/doi.org\/10.1002\/bit.26845","journal-title":"Biotechnol Bioeng"},{"issue":"6","key":"4315_CR35","doi-asserted-by":"publisher","first-page":"369","DOI":"10.7164\/antibiotics.25.369","volume":"25","author":"H Otsuka","year":"1972","unstructured":"Otsuka H, Niwayama S, Tanaka H et al (1972) An antitumor antibiotic, 4601 from streptomyces, identical with Yc 73 of Pseudomonas origin. J Antibiot 25(6):369\u2013370. https:\/\/doi.org\/10.7164\/antibiotics.25.369","journal-title":"J Antibiot"},{"issue":"6","key":"4315_CR36","doi-asserted-by":"publisher","first-page":"988","DOI":"10.1039\/d0mt00084a","volume":"12","author":"S Parveen","year":"2020","unstructured":"Parveen S, Cowan JA, Yu Z, Arjmand F (2020) Enantiomeric copper based anticancer agents promoting sequence-selective cleavage of G-quadruplex telomeric DNA and non-random cleavage of plasmid DNA. Metallomics 12(6):988\u2013999. https:\/\/doi.org\/10.1039\/d0mt00084a","journal-title":"Metallomics"},{"issue":"9","key":"4315_CR37","doi-asserted-by":"publisher","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","volume":"29","author":"MW Pfaffl","year":"2001","unstructured":"Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT\u2013PCR. Nucleic Acids Res 29(9):e45. https:\/\/doi.org\/10.1093\/nar\/29.9.e45","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"4315_CR39","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.cmpb.2015.02.006","volume":"119","author":"F Piccinini","year":"2015","unstructured":"Piccinini F (2015) AnaSP: a software suite for automatic image analysis of multicellular spheroids. Comput Methods Programs Biomed 119(1):43\u201352. https:\/\/doi.org\/10.1016\/j.cmpb.2015.02.006","journal-title":"Comput Methods Programs Biomed"},{"issue":"2","key":"4315_CR38","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.cmpb.2014.12.003","volume":"118","author":"F Piccinini","year":"2015","unstructured":"Piccinini F, Tesei A, Arienti C, Alessandro B (2015) Cancer multicellular spheroids: volume assessment from a single 2D projection. Comput Methods Programs Biomed 118(2):95\u2013106. https:\/\/doi.org\/10.1016\/j.cmpb.2014.12.003","journal-title":"Comput Methods Programs Biomed"},{"issue":"Pt 1","key":"4315_CR40","doi-asserted-by":"publisher","first-page":"133323","DOI":"10.1016\/j.ijbiomac.2024.133323","volume":"274","author":"J Qin","year":"2024","unstructured":"Qin J, Li Z, Su L et al (2024) Expression of transferrin receptor\/TFRC protein in bladder cancer cell T24 and its role in inducing iron death in bladder cancer. Int J Biol Macromol 274(Pt 1):133323. https:\/\/doi.org\/10.1016\/j.ijbiomac.2024.133323","journal-title":"Int J Biol Macromol"},{"issue":"1","key":"4315_CR41","doi-asserted-by":"publisher","first-page":"14579","DOI":"10.1038\/s41598-021-93780-x","volume":"11","author":"P Ror\u00edguez-Jim\u00e9nez","year":"2021","unstructured":"Ror\u00edguez-Jim\u00e9nez P, Fern\u00e1ndez-Messina L, Ovejero-Benito MC et al (2021) Growth arrest and DNA damage-inducible proteins (GADD45) in psoriasis. Sci Rep 11(1):14579. https:\/\/doi.org\/10.1038\/s41598-021-93780-x","journal-title":"Sci Rep"},{"issue":"1","key":"4315_CR42","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/febs.14712","volume":"286","author":"P S\u00e1nchez-Mart\u00edn","year":"2019","unstructured":"S\u00e1nchez-Mart\u00edn P, Saito T, Komatsu M (2019) p62\/SQSTM1: \u2018Jack of all trades\u2019 in health and cancer. FEBS J 286(1):8\u201323. https:\/\/doi.org\/10.1111\/febs.14712","journal-title":"FEBS J"},{"key":"4315_CR43","doi-asserted-by":"publisher","unstructured":"Sangeetha S, Murali M (2018) Non-covalent DNA binding, protein interaction, DNA cleavage and cytotoxicity of [Cu(quamol)Cl]\u00b7H2O. Int J Biol Macromol 107(Pt B) 2501\u20132511. https:\/\/doi.org\/10.1016\/j.ijbiomac.2017.10.131","DOI":"10.1016\/j.ijbiomac.2017.10.131"},{"issue":"1","key":"4315_CR44","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1007\/s12672-023-00738-8","volume":"14","author":"L Song","year":"2023","unstructured":"Song L, Zeng R, Yang K et al (2023) The biological significance of cuproptosis-key gene MTF1 in pan-cancer and its inhibitory effects on ROS-mediated cell death of liver hepatocellular carcinoma. Discov Oncol 14(1):113. https:\/\/doi.org\/10.1007\/s12672-023-00738-8","journal-title":"Discov Oncol"},{"issue":"26","key":"4315_CR45","doi-asserted-by":"publisher","first-page":"14376","DOI":"10.1073\/pnas.97.26.14376","volume":"97","author":"S Sperandio","year":"2000","unstructured":"Sperandio S, De Belle I, Bredesen DE (2000) An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci 97(26):14376\u201314381. https:\/\/doi.org\/10.1073\/pnas.97.26.14376","journal-title":"Proc Natl Acad Sci"},{"issue":"6","key":"4315_CR46","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1016\/j.nano.2017.04.009","volume":"13","author":"J Tang","year":"2017","unstructured":"Tang J, Kuai R, Yuan W et al (2017) Effect of size and pegylation of liposomes and peptide-based synthetic lipoproteins on tumor targeting. Nanomed Nanotechnol Biol Med 13(6):1869\u20131878. https:\/\/doi.org\/10.1016\/j.nano.2017.04.009","journal-title":"Nanomed Nanotechnol Biol Med"},{"issue":"6586","key":"4315_CR47","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.1126\/science.abf0529","volume":"375","author":"P Tsvetkov","year":"2022","unstructured":"Tsvetkov P, Coy S, Petrova B et al (2022) Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 375(6586):1254\u20131261. https:\/\/doi.org\/10.1126\/science.abf0529","journal-title":"Science"},{"key":"4315_CR48","doi-asserted-by":"publisher","unstructured":"Vandesompele J, De Preter K, Pattyn F et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3(7):research0034. https:\/\/doi.org\/10.1186\/gb-2002-3-7-research0034","DOI":"10.1186\/gb-2002-3-7-research0034"},{"issue":"7782","key":"4315_CR49","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1038\/s41586-019-1730-1","volume":"575","author":"N Vasan","year":"2019","unstructured":"Vasan N, Baselga J, Hyman DM (2019) A view on drug resistance in cancer. Nature 575(7782):299\u2013309. https:\/\/doi.org\/10.1038\/s41586-019-1730-1","journal-title":"Nature"},{"key":"4315_CR50","doi-asserted-by":"publisher","first-page":"104643","DOI":"10.1016\/j.tiv.2019.104643","volume":"61","author":"TA Zanetti","year":"2019","unstructured":"Zanetti TA, Biazi BI, Coatti GC et al (2019) Mitotic spindle defects and DNA damage induced by dimethoxycurcumin lead to an intrinsic apoptosis pathway in HepG2\/C3A cells. Toxicol Vitro 61:104643. https:\/\/doi.org\/10.1016\/j.tiv.2019.104643","journal-title":"Toxicol Vitro"},{"key":"4315_CR51","doi-asserted-by":"publisher","first-page":"806081","DOI":"10.3389\/fcell.2022.806081","volume":"10","author":"Q Zhang","year":"2022","unstructured":"Zhang Q, Qu H, Chen Y et al (2022) Atorvastatin induces mitochondria-dependent ferroptosis via the modulation of Nrf2-xCT\/GPx4 axis. Front Cell Dev Biol 10:806081. https:\/\/doi.org\/10.3389\/fcell.2022.806081","journal-title":"Front Cell Dev Biol"},{"key":"4315_CR52","doi-asserted-by":"publisher","first-page":"992468","DOI":"10.3389\/fonc.2022.992468","volume":"12","author":"X Zhao","year":"2022","unstructured":"Zhao X, Chen J, Yin S et al (2022a) The expression of cuproptosis-related genes in hepatocellular carcinoma and their relationships with prognosis. Front Oncol 12:992468. https:\/\/doi.org\/10.3389\/fonc.2022.992468","journal-title":"Front Oncol"},{"issue":"1","key":"4315_CR53","doi-asserted-by":"publisher","first-page":"e24118","DOI":"10.1002\/jcla.24118","volume":"36","author":"Z Zhao","year":"2022","unstructured":"Zhao Z, Wan J, Guo M et al (2022b) Expression and prognostic significance of m6A-related genes in TP53\u2010mutant non\u2010small\u2010cell lung cancer. J C Lab Anal 36(1):e24118. https:\/\/doi.org\/10.1002\/jcla.24118","journal-title":"J C Lab Anal"},{"issue":"1","key":"4315_CR54","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1166\/jbt.2021.2386","volume":"11","author":"S Zheng","year":"2021","unstructured":"Zheng S, Yang H, Chang Y et al (2021) Effect of the BBC3 gene on the proliferation and apoptosis of hepatocellular carcinoma cells through p53-Regulated signaling. J Biomat Tissue Eng 11(1):135\u2013141. https:\/\/doi.org\/10.1166\/jbt.2021.2386","journal-title":"J Biomat Tissue Eng"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-026-04315-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-026-04315-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-026-04315-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T18:58:20Z","timestamp":1781636300000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-026-04315-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,27]]},"references-count":54,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5]]}},"alternative-id":["4315"],"URL":"https:\/\/doi.org\/10.1007\/s00204-026-04315-0","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,27]]},"assertion":[{"value":"19 November 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 January 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 February 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}