{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T11:09:46Z","timestamp":1792840186825,"version":"4.5.0"},"reference-count":75,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T00:00:00Z","timestamp":1766707200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":12,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Non-genetic resistance of cancer remains poorly understood in clinical research and practice. To better understand resistant cancer cell heterogeneity, we isolated a novel riboflavin\n                    <jats:sup>+<\/jats:sup>\n                    NOTCH1\n                    <jats:sup>+<\/jats:sup>\n                    population from cisplatin-na\u00efve and -resistant lung cancer cell lines and patient specimens with or without immunotherapy and chemotherapy. This population was also identified as\n                    <jats:italic>SLC52A2<\/jats:italic>\n                    (one of the riboflavin transporters)\n                    <jats:sup>+<\/jats:sup>\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>+<\/jats:italic>\n                    <\/jats:sup>\n                    cells in single-cell RNA sequencing (scRNA-seq) data derived from advanced lung tumors before therapy. Despite its therapy-na\u00efve origin, the population, designated as stably resistant cancer cells (SRCC), exhibited the epithelial state, innate and stable resistance to therapy (chemotherapy, targeted therapy and immunotherapy), cell dormancy, elevated reactive oxygen species (ROS), and anti-apoptotic and anti-ferroptotic survival. These cellular and molecular characteristics distinguished SRCC from other resistant populations, including cancer stem-like cells (CSC), epithelial-mesenchymal transition (EMT) cells, and drug-tolerant persisters (DTP). The non-canonical NOTCH1 pathway, but not the inactivated canonical NOTCH1 pathway, played a critical role in the resistance of SRCC. Specifically, it modulates cell cycle, iron metabolism, EMT, and ferroptosis vulnerability in SRCC at the transcriptional level. It also controls the initiation of ferroptosis in lysosomes via a posttranslational NOTCH1-AKT-BAX axis. Inhibition of the non-canonical NOTCH1 pathway re-sensitizes these dormant and resistant cells to cisplatin-induced cell death in vitro and in vivo, including ferroptosis, apoptosis, and necroptosis. Our study contributes to a deeper understanding of cancer resistance and promotes the development of more effective therapeutic strategies against resistant cancer cells.\n                  <\/jats:p>","DOI":"10.1038\/s41419-025-08355-9","type":"journal-article","created":{"date-parts":[[2025,12,26]],"date-time":"2025-12-26T19:55:41Z","timestamp":1766778941000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Non-canonical NOTCH1 signaling regulates ferroptosis vulnerability in dormant lung cancer cells with stable resistance"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6586-3857","authenticated-orcid":false,"given":"Hongli","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Chai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1047-0041","authenticated-orcid":false,"given":"Xuewei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5364-7179","authenticated-orcid":false,"given":"Sen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6219-9376","authenticated-orcid":false,"given":"Binglin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2718-1549","authenticated-orcid":false,"given":"Wen","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9351-1720","authenticated-orcid":false,"given":"Yuefeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5186-4165","authenticated-orcid":false,"given":"Hua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1990-7265","authenticated-orcid":false,"given":"Zhengliang","family":"Tu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5753-6234","authenticated-orcid":false,"given":"Chengli","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiayi","family":"Lyu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7910-5387","authenticated-orcid":false,"given":"Guiying","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2226-2613","authenticated-orcid":false,"given":"Wei","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,26]]},"reference":[{"key":"8355_CR1","doi-asserted-by":"publisher","first-page":"1824","DOI":"10.1001\/jamaoncol.2021.4932","volume":"7","author":"AK Ganti","year":"2021","unstructured":"Ganti AK, Klein AB, Cotarla I, Seal B, Chou E. Update of incidence, prevalence, survival, and initial treatment in patients with non\u2013small cell lung cancer in the US. JAMA Oncol. 2021;7:1824\u201332.","journal-title":"JAMA Oncol"},{"key":"8355_CR2","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/S0140-6736(16)30958-8","volume":"389","author":"FR Hirsch","year":"2017","unstructured":"Hirsch FR, Scagliotti GV, Mulshine JL, Kwon R, Curran WJ, Wu Y-L, et al. Lung cancer: current therapies and new targeted treatments. Lancet. 2017;389:299\u2013311.","journal-title":"Lancet"},{"key":"8355_CR3","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1126\/science.1062538","volume":"293","author":"ME Gorre","year":"2001","unstructured":"Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876\u201380.","journal-title":"Science"},{"key":"8355_CR4","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1038\/s41568-020-00302-4","volume":"20","author":"J-C Marine","year":"2020","unstructured":"Marine J-C, Dawson S-J, Dawson MA. Non-genetic mechanisms of therapeutic resistance in cancer. Nat Rev Cancer. 2020;20:743\u201356.","journal-title":"Nat Rev Cancer"},{"key":"8355_CR5","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.stem.2024.04.004","volume":"31","author":"J-J Loh","year":"2024","unstructured":"Loh J-J, Ma S. Hallmarks of cancer stemness. Cell Stem Cell. 2024;31:617\u201339.","journal-title":"Cell Stem Cell"},{"key":"8355_CR6","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.cell.2016.06.028","volume":"166","author":"MA Nieto","year":"2016","unstructured":"Nieto MA, Huang RY-J, Jackson RA, Thiery JP. EMT: 2016. Cell. 2016;166:21\u201345.","journal-title":"Cell"},{"key":"8355_CR7","doi-asserted-by":"publisher","first-page":"3203","DOI":"10.1016\/j.devcel.2021.11.006","volume":"56","author":"F L\u00fc\u00f6nd","year":"2021","unstructured":"L\u00fc\u00f6nd F, Sugiyama N, Bill R, Bornes L, Hager C, Tang F, et al. Distinct contributions of partial and full EMT to breast cancer malignancy. Dev Cell. 2021;56:3203\u20133221.e11.","journal-title":"Dev Cell"},{"key":"8355_CR8","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.cell.2010.02.027","volume":"141","author":"SV Sharma","year":"2010","unstructured":"Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69\u201380.","journal-title":"Cell"},{"key":"8355_CR9","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1038\/nm0797-730","volume":"3","author":"D Bonnet","year":"1997","unstructured":"Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730\u20137.","journal-title":"Nat Med"},{"key":"8355_CR10","doi-asserted-by":"publisher","first-page":"3983","DOI":"10.1073\/pnas.0530291100","volume":"100","author":"M Al-Hajj","year":"2003","unstructured":"Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983\u20138.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8355_CR11","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-022-09953-y","volume":"22","author":"J Yin","year":"2022","unstructured":"Yin J, Wen Y, Zeng J, Zhang Y, Chen J, Zhang Y, et al. CDC50A might be a novel biomarker of epithelial ovarian cancer-initiating cells. BMC Cancer. 2022;22:903.","journal-title":"BMC Cancer"},{"key":"8355_CR12","doi-asserted-by":"publisher","first-page":"3082","DOI":"10.1158\/0008-5472.CAN-16-1633","volume":"77","author":"Y Zhang","year":"2017","unstructured":"Zhang Y, Xu W, Guo H, Zhang Y, He Y, Lee SH, et al. NOTCH1 signaling regulates self-renewal and platinum chemoresistance of cancer stem-like cells in human non-small cell lung cancer. Cancer Res. 2017;77:3082\u201391.","journal-title":"Cancer Res"},{"key":"8355_CR13","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1038\/nature06933","volume":"453","author":"W Guo","year":"2008","unstructured":"Guo W, Lasky JL, Chang C-J, Mosessian S, Lewis X, Xiao Y, et al. Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature. 2008;453:529\u201333.","journal-title":"Nature"},{"key":"8355_CR14","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/nrclinonc.2013.158","volume":"10","author":"EA Kuczynski","year":"2013","unstructured":"Kuczynski EA, Sargent DJ, Grothey A, Kerbel RS. Drug rechallenge and treatment beyond progression\u2014implications for drug resistance. Nat Rev Clin Oncol. 2013;10:571\u201387.","journal-title":"Nat Rev Clin Oncol"},{"key":"8355_CR15","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1152\/physrev.00005.2017","volume":"97","author":"C Siebel","year":"2017","unstructured":"Siebel C, Lendahl U. Notch signaling in development, tissue homeostasis, and disease. Physiol Rev. 2017;97:1235\u201394.","journal-title":"Physiol Rev"},{"key":"8355_CR16","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.ccr.2014.02.018","volume":"25","author":"P Ntziachristos","year":"2014","unstructured":"Ntziachristos P, Lim JS, Sage J, Aifantis I. From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell. 2014;25:318\u201334.","journal-title":"Cancer Cell"},{"key":"8355_CR17","doi-asserted-by":"publisher","first-page":"22293","DOI":"10.1073\/pnas.0907781106","volume":"106","author":"B Westhoff","year":"2009","unstructured":"Westhoff B, Colaluca IN, D\u2019Ario G, Donzelli M, Tosoni D, Volorio S, et al. Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci USA. 2009;106:22293\u20138.","journal-title":"Proc Natl Acad Sci USA"},{"key":"8355_CR18","doi-asserted-by":"crossref","unstructured":"Zhang H, Liang J, Lu T, Li M, Shan G, Bi G, et al. AGRN promotes lung adenocarcinoma progression by activating Notch signaling pathway and acts as a therapeutic target. Pharmacol Res. 2023;194:106819.","DOI":"10.1016\/j.phrs.2023.106819"},{"key":"8355_CR19","doi-asserted-by":"publisher","first-page":"5974","DOI":"10.1158\/0008-5472.CAN-13-1384","volume":"73","author":"S Licciulli","year":"2013","unstructured":"Licciulli S, Avila JL, Hanlon L, Troutman S, Cesaroni M, Kota S, et al. Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53. Cancer Res. 2013;73:5974\u201384.","journal-title":"Cancer Res"},{"key":"8355_CR20","doi-asserted-by":"crossref","unstructured":"Xie M, He C-S, Wei S-H, Zhang L. Notch-1 contributes to epidermal growth factor receptor tyrosine kinase inhibitor acquired resistance in non-small cell lung cancer in vitro and in vivo. Eur J Cancer. 2013;49:3559\u201372.","DOI":"10.1016\/j.ejca.2013.07.007"},{"key":"8355_CR21","doi-asserted-by":"publisher","first-page":"612","DOI":"10.1172\/JCI126896","volume":"130","author":"E Bousquet Mur","year":"2020","unstructured":"Bousquet Mur E, Bernardo S, Papon L, Mancini M, Fabbrizio E, Goussard M, et al. Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma. J Clin Invest. 2020;130:612\u201324.","journal-title":"J Clin Invest"},{"key":"8355_CR22","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3389\/fonc.2014.00040","volume":"4","author":"M McDermott","year":"2014","unstructured":"McDermott M, Eustace A, Busschots S, Breen L, Clynes M, O\u2019Donovan N, et al. In vitro Development of Chemotherapy and Targeted Therapy Drug-Resistant Cancer Cell Lines: A Practical Guide with Case Studies. Front Oncol. 2014;4:40.","journal-title":"Front Oncol"},{"key":"8355_CR23","doi-asserted-by":"publisher","first-page":"e0184578","DOI":"10.1371\/journal.pone.0184578","volume":"12","author":"D Liu","year":"2017","unstructured":"Liu D, Hu Y, Guo Y, Zhu Z, Lu B, Wang X, et al. Mycoplasma-associated multidrug resistance of hepatocarcinoma cells requires the interaction of P37 and Annexin A2. PLOS ONE. 2017;12:e0184578.","journal-title":"PLOS ONE"},{"key":"8355_CR24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-42809-y","volume":"14","author":"JM Stillman","year":"2023","unstructured":"Stillman JM, Mendes Lopes F, Lin J-P, Hu K, Reich DS, Schafer DP. Lipofuscin-like autofluorescence within microglia and its impact on studying microglial engulfment. Nat Commun. 2023;14:7060.","journal-title":"Nat Commun"},{"key":"8355_CR25","doi-asserted-by":"publisher","first-page":"1952","DOI":"10.3390\/ijms14011952","volume":"14","author":"MS Islam","year":"2013","unstructured":"Islam MS, Honma M, Nakabayashi T, Kinjo M, Ohta N. pH dependence of the fluorescence lifetime of FAD in solution and in cells. Int J Mol Sci. 2013;14:1952\u201363.","journal-title":"Int J Mol Sci"},{"key":"8355_CR26","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1089\/ars.2017.7451","volume":"30","author":"OI Kolenc","year":"2019","unstructured":"Kolenc OI, Quinn KP. Evaluating cell metabolism through autofluorescence imaging of NAD(P)H and FAD. Antioxid Redox Sign. 2019;30:875\u201389.","journal-title":"Antioxid Redox Sign"},{"key":"8355_CR27","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.mam.2012.07.014","volume":"34","author":"A Yonezawa","year":"2013","unstructured":"Yonezawa A, Inui K. Novel riboflavin transporter family RFVT\/SLC52: identification, nomenclature, functional characterization and genetic diseases of RFVT\/SLC52. Mol Aspects Med. 2013;34:693\u2013701.","journal-title":"Mol Aspects Med"},{"key":"8355_CR28","doi-asserted-by":"publisher","first-page":"5329","DOI":"10.1111\/jcmm.14409","volume":"23","author":"R Yang","year":"2019","unstructured":"Yang R, Wei Z, Wu S. Lumiflavin increases the sensitivity of ovarian cancer stem-like cells to cisplatin by interfering with riboflavin. J Cell Mol Med. 2019;23:5329\u201339.","journal-title":"J Cell Mol Med"},{"key":"8355_CR29","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1038\/nmeth.3112","volume":"11","author":"I Miranda-Lorenzo","year":"2014","unstructured":"Miranda-Lorenzo I, Dorado J, Lonardo E, Alcala S, Serrano AG, Clausell-Tormos J, et al. Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nat Methods. 2014;11:1161\u20139.","journal-title":"Nat Methods"},{"key":"8355_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21884-z","volume":"12","author":"Aissa","year":"2021","unstructured":"Aissa, Islam AF, ABMMK, Ariss MM, Go CC, Rader AE, Conrardy RD, et al. Single-cell transcriptional changes associated with drug tolerance and response to combination therapies in cancer. Nat Commun. 2021;12:1628.","journal-title":"Nat Commun"},{"key":"8355_CR31","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/nature07733","volume":"458","author":"M Diehn","year":"2009","unstructured":"Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature. 2009;458:780\u20133.","journal-title":"Nature"},{"key":"8355_CR32","doi-asserted-by":"crossref","unstructured":"Rizzollo F, More S, Vangheluwe P, Agostinis P. The lysosome as a master regulator of iron metabolism. Trends Biochem Sci. 2021;46:960\u201375.","DOI":"10.1016\/j.tibs.2021.07.003"},{"key":"8355_CR33","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1093\/nar\/gkh541","volume":"32","author":"G Wang","year":"2004","unstructured":"Wang G, Chuang L, Zhang X, Colton S, Dombkowski A, Reiners J, et al. The initiative role of XPC protein in cisplatin DNA damaging treatment-mediated cell cycle regulation. Nucleic Acids Res. 2004;32:2231\u201340.","journal-title":"Nucleic Acids Res"},{"key":"8355_CR34","doi-asserted-by":"publisher","first-page":"8361","DOI":"10.1038\/sj.onc.1206016","volume":"21","author":"A Brachat","year":"2002","unstructured":"Brachat A, Pierrat B, Xynos A, Brecht K, Simonen M, Br\u00fcngger A, et al. A microarray-based, integrated approach to identify novel regulators of cancer drug response and apoptosis. Oncogene. 2002;21:8361\u201371.","journal-title":"Oncogene"},{"key":"8355_CR35","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1158\/1078-0432.CCR-1025-3","volume":"10","author":"HC Kang","year":"2004","unstructured":"Kang HC, Kim I-J, Park J-H, Shin Y, Ku J-L, Jung MS, et al. Identification of genes with differential expression in acquired drug-resistant gastric cancer cells using high-density oligonucleotide microarrays. Clin Cancer Res. 2004;10:272\u201384.","journal-title":"Clin Cancer Res"},{"key":"8355_CR36","doi-asserted-by":"publisher","first-page":"6090","DOI":"10.1038\/sj.onc.1208755","volume":"24","author":"JS Kerley-Hamilton","year":"2005","unstructured":"Kerley-Hamilton JS, Pike AM, Li N, DiRenzo J, Spinella MJ. A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embryonal carcinoma. Oncogene. 2005;24:6090\u2013100.","journal-title":"Oncogene"},{"key":"8355_CR37","doi-asserted-by":"publisher","first-page":"6395","DOI":"10.1038\/s41388-021-02055-2","volume":"40","author":"D Huang","year":"2021","unstructured":"Huang D, Savage SR, Calinawan AP, Lin C, Zhang B, Wang P, et al. A highly annotated database of genes associated with platinum resistance in cancer. Oncogene. 2021;40:6395\u2013405.","journal-title":"Oncogene"},{"key":"8355_CR38","doi-asserted-by":"publisher","first-page":"1470","DOI":"10.1038\/s41556-024-01464-1","volume":"26","author":"A Schwab","year":"2024","unstructured":"Schwab A, Rao Z, Zhang J, Gollowitzer A, Siebenk\u00e4s K, Bindel N, et al. Zeb1 mediates EMT\/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition. Nat Cell Biol. 2024;26:1470\u201381.","journal-title":"Nat Cell Biol"},{"key":"8355_CR39","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1016\/j.ccell.2024.04.009","volume":"42","author":"Y Liu","year":"2024","unstructured":"Liu Y, Su Z, Tavana O, Gu W. Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell. 2024;42:946\u201367.","journal-title":"Cancer Cell"},{"key":"8355_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-32552-1","volume":"13","author":"D Saul","year":"2022","unstructured":"Saul D, Kosinsky RL, Atkinson EJ, Doolittle ML, Zhang X, LeBrasseur NK, et al. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nat Commun. 2022;13:4827.","journal-title":"Nat Commun"},{"key":"8355_CR41","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.645593","volume":"9","author":"R Kumari","year":"2021","unstructured":"Kumari R, Jat P. Mechanisms of cellular senescence: Cell cycle arrest and senescence associated secretory phenotype. Front Cell Dev Biol. 2021;9:645593.","journal-title":"Front Cell Dev Biol"},{"key":"8355_CR42","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/S1535-6108(03)00080-1","volume":"3","author":"H Cam","year":"2003","unstructured":"Cam H, Dynlacht BD. Emerging roles for E2F: Beyond the G1\/S transition and DNA replication. Cancer Cell. 2003;3:311\u20136.","journal-title":"Cancer Cell"},{"key":"8355_CR43","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1128\/MCB.24.1.200-216.2004","volume":"24","author":"DC Fingar","year":"2004","unstructured":"Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1\/eukaryotic translation initiation factor 4E. Mol Cell Bio. 2004;24:200\u201316.","journal-title":"Mol Cell Bio"},{"key":"8355_CR44","doi-asserted-by":"publisher","first-page":"5083","DOI":"10.1002\/j.1460-2075.1993.tb06202.x","volume":"12","author":"B Amati","year":"1993","unstructured":"Amati B, Littlewood TD, Evan GI, Land H. The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 1993;12:5083\u20137.","journal-title":"EMBO J"},{"key":"8355_CR45","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-023-02963-4","volume":"24","author":"AJ Wiecek","year":"2023","unstructured":"Wiecek AJ, Cutty SJ, Kornai D, Parreno-Centeno M, Gourmet LE, Tagliazucchi GM, et al. Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer. Genome Biol. 2023;24:128.","journal-title":"Genome Biol"},{"key":"8355_CR46","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/j.stem.2016.01.013","volume":"18","author":"J Hur","year":"2016","unstructured":"Hur J, Choi J-I, Lee H, Nham P, Kim T-W, Chae C-W, et al. CD82\/KAI1 maintains the dormancy of long-term hematopoietic stem cells through interaction with DARC-expressing macrophages. Cell Stem Cell. 2016;18:508\u201321.","journal-title":"Cell Stem Cell"},{"key":"8355_CR47","doi-asserted-by":"publisher","first-page":"1396","DOI":"10.1182\/blood-2019-129320","volume":"134","author":"M Floren","year":"2019","unstructured":"Floren M, Pascetti E, Gillette J. The membrane scaffold CD82 regulates acute myeloid leukemia dormancy and bone marrow niche interactions. Blood. 2019;134:1396.","journal-title":"Blood"},{"key":"8355_CR48","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.cmet.2019.12.007","volume":"31","author":"MM Santoro","year":"2020","unstructured":"Santoro MM. The antioxidant role of non-mitochondrial CoQ10: mystery solved!. Cell Metabolism. 2020;31:13\u20135.","journal-title":"Cell Metabolism"},{"key":"8355_CR49","doi-asserted-by":"crossref","unstructured":"Kim N, Kim HK, Lee K, Hong Y, Cho JH, Choi JW, et al. Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma. Nat Commun. 2020;11:2285.","DOI":"10.1038\/s41467-020-16164-1"},{"key":"8355_CR50","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-51891-9","volume":"15","author":"Y Xu","year":"2024","unstructured":"Xu Y, Wang S, Feng Q, Xia J, Li Y, Li H-D, et al. scCAD: Cluster decomposition-based anomaly detection for rare cell identification in single-cell expression data. Nat Commun. 2024;15:7561.","journal-title":"Nat Commun"},{"key":"8355_CR51","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1016\/j.ccell.2024.08.005","volume":"42","author":"I Tirosh","year":"2024","unstructured":"Tirosh I, Suva ML. Cancer cell states: Lessons from ten years of single-cell RNA-sequencing of human tumors. Cancer Cell. 2024;42:1497\u2013506.","journal-title":"Cancer Cell"},{"key":"8355_CR52","doi-asserted-by":"publisher","first-page":"6882","DOI":"10.1073\/pnas.0910060107","volume":"107","author":"LR Perumalsamy","year":"2010","unstructured":"Perumalsamy LR, Nagala M, Sarin A. Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival. Proc Nal Acad Sci. 2010;107:6882\u20137.","journal-title":"Proc Nal Acad Sci"},{"key":"8355_CR53","doi-asserted-by":"crossref","unstructured":"Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, et al. Preclinical profile of a potent \u03b3-secretase inhibitor targeting Notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res. 2009;69:7672\u201380.","DOI":"10.1158\/0008-5472.CAN-09-1843"},{"key":"8355_CR54","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/s41580-024-00703-5","volume":"25","author":"SJ Dixon","year":"2024","unstructured":"Dixon SJ, Olzmann JA. The cell biology of ferroptosis. Nat Rev Mol Cell Biol. 2024;25:424\u201342.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"8355_CR55","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.590226","volume":"8","author":"X Chen","year":"2020","unstructured":"Chen X, Yu C, Kang R, Tang D. Iron metabolism in ferroptosis. Front Cell Dev Biol. 2020;8:590226.","journal-title":"Front Cell Dev Biol"},{"key":"8355_CR56","doi-asserted-by":"crossref","unstructured":"Seiler A, Schneider M, F\u00f6rster H, Roth S, Wirth EK, Culmsee C, et al. Glutathione Peroxidase 4 Senses and Translates Oxidative Stress into 12\/15-Lipoxygenase Dependent- and AIF-Mediated Cell Death. Cell Metab. 2008;8:237\u201348.","DOI":"10.1016\/j.cmet.2008.07.005"},{"key":"8355_CR57","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1016\/j.chembiol.2022.06.004","volume":"29","author":"L Magtanong","year":"2022","unstructured":"Magtanong L, Mueller GD, Williams KJ, Billmann M, Chan K, Armenta DA, et al. Context-dependent regulation of ferroptosis sensitivity. Cell Chem Biol. 2022;29:1409\u20131418.e6.","journal-title":"Cell Chem Biol"},{"key":"8355_CR58","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-58909-w","volume":"16","author":"Y Saimoto","year":"2025","unstructured":"Saimoto Y, Kusakabe D, Morimoto K, Matsuoka Y, Kozakura E, Kato N, et al. Lysosomal lipid peroxidation contributes to ferroptosis induction via lysosomal membrane permeabilization. Nat Commun. 2025;16:3554.","journal-title":"Nat Commun"},{"key":"8355_CR59","doi-asserted-by":"crossref","unstructured":"Ca\u00f1eque T, Baron L, M\u00fcller S, Carmona A, Colombeau L, Versini A, et al. Activation of lysosomal iron triggers ferroptosis in cancer. Nature. 2025;642:492\u2013500.","DOI":"10.1038\/s41586-025-08974-4"},{"key":"8355_CR60","doi-asserted-by":"crossref","unstructured":"Karch J, Schips TG, Maliken BD, Brody MJ, Sargent MA, Kanisicak O, et al. Autophagic cell death is dependent on lysosomal membrane permeability through Bax and Bak. eLife. 2017;6:e30543.","DOI":"10.7554\/eLife.30543"},{"key":"8355_CR61","doi-asserted-by":"crossref","unstructured":"Yamaguchi H, Wang H-G. The protein kinase PKB\/Akt regulates cell survival and apoptosis by inhibiting Bax conformational change. Oncogene. 2001;20:7779\u201386.","DOI":"10.1038\/sj.onc.1204984"},{"key":"8355_CR62","doi-asserted-by":"publisher","first-page":"445","DOI":"10.4143\/crt.2016.572","volume":"50","author":"J Guo","year":"2017","unstructured":"Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, et al. Ferroptosis: A novel anti-tumor action for cisplatin. Cancer Res Treat. 2017;50:445\u201360.","journal-title":"Cancer Res Treat"},{"key":"8355_CR63","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1016\/j.ymthe.2024.02.029","volume":"32","author":"Z Liu","year":"2024","unstructured":"Liu Z, Zhang H, Hong G, Bi X, Hu J, Zhang T, et al. Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL\/6 mice. Mol Ther. 2024;32:1387\u2013406.","journal-title":"Mol Ther"},{"key":"8355_CR64","doi-asserted-by":"crossref","unstructured":"Wang X, Xu L, Meng Y, Chen F, Zhuang J, Wang M, et al. FOXO1-NCOA4 axis contributes to cisplatin-induced cochlea spiral ganglion neuron ferroptosis via ferritinophagy. Adv Sci. 2024;11:2402671.","DOI":"10.1002\/advs.202402671"},{"key":"8355_CR65","doi-asserted-by":"publisher","first-page":"20116","DOI":"10.1016\/S0021-9258(20)80702-9","volume":"268","author":"T Ishikawa","year":"1993","unstructured":"Ishikawa T, Ali-Osman F. Glutathione-associated cis-diamminedichloroplatinum(II) metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization of glutathione-platinum complex and its biological significance. J Biol Chem. 1993;268:20116\u201325.","journal-title":"J Biol Chem"},{"key":"8355_CR66","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1158\/1535-7163.MCT-10-0034","volume":"9","author":"P Wei","year":"2010","unstructured":"Wei P, Walls M, Qiu M, Ding R, Denlinger RH, Wong A, et al. Evaluation of selective \u03b3-secretase inhibitor PF-03084014 for its antitumor efficacy and gastrointestinal safety to guide optimal clinical trial design. Mol Cancer Ther. 2010;9:1618\u201328.","journal-title":"Mol Cancer Ther"},{"key":"8355_CR67","doi-asserted-by":"publisher","first-page":"1798","DOI":"10.1016\/j.jtho.2021.07.017","volume":"16","author":"M Mikubo","year":"2021","unstructured":"Mikubo M, Inoue Y, Liu G, Tsao M-S. Mechanism of drug tolerant persister cancer cells: The landscape and clinical implication for therapy. J Thorac Oncol. 2021;16:1798\u2013809.","journal-title":"J Thorac Oncol"},{"key":"8355_CR68","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/s41568-020-0263-0","volume":"20","author":"TG Phan","year":"2020","unstructured":"Phan TG, Croucher PI. The dormant cancer cell life cycle. Nat Rev Cancer. 2020;20:398\u2013411.","journal-title":"Nat Rev Cancer"},{"key":"8355_CR69","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/s41568-023-00642-x","volume":"24","author":"J Agudo","year":"2024","unstructured":"Agudo J, Aguirre-Ghiso JA, Bhatia M, Chodosh LA, Correia AL, Klein CA. Targeting cancer cell dormancy. Nat Rev Cancer. 2024;24:97\u2013104.","journal-title":"Nat Rev Cancer"},{"key":"8355_CR70","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/s41388-021-02107-7","volume":"41","author":"T Bui","year":"2022","unstructured":"Bui T, Gu Y, Ancot F, Sanguin-Gendreau V, Zuo D, Muller WJ. Emergence of \u03b21 integrin-deficient breast tumours from dormancy involves both inactivation of p53 and generation of a permissive tumour microenvironment. Oncogene. 2022;41:527\u201337.","journal-title":"Oncogene"},{"key":"8355_CR71","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/s13045-014-0087-z","volume":"7","author":"X Yuan","year":"2014","unstructured":"Yuan X, Wu H, Han N, Xu H, Chu Q, Yu S, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol. 2014;7:87.","journal-title":"J Hematol Oncol"},{"key":"8355_CR72","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01500-9","volume":"8","author":"M Natsuizaka","year":"2017","unstructured":"Natsuizaka M, Whelan KA, Kagawa S, Tanaka K, Giroux V, Chandramouleeswaran PM, et al. Interplay between Notch1 and Notch3 promotes EMT and tumor initiation in squamous cell carcinoma. Nat Commun. 2017;8:1758.","journal-title":"Nat Commun"},{"key":"8355_CR73","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04070-6","volume":"9","author":"L Vera-Ramirez","year":"2018","unstructured":"Vera-Ramirez L, Vodnala SK, Nini R, Hunter KW, Green JE. Autophagy promotes the survival of dormant breast cancer cells and metastatic tumour recurrence. Nat Commun. 2018;9:1944.","journal-title":"Nat Commun"},{"key":"8355_CR74","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1007\/BF00300234","volume":"24","author":"MM Tomayko","year":"1989","unstructured":"Tomayko MM, Reynolds CP. Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 1989;24:148\u201354.","journal-title":"Cancer Chemother Pharmacol"},{"key":"8355_CR75","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1038\/nri1416","volume":"4","author":"SP Perfetto","year":"2004","unstructured":"Perfetto SP, Chattopadhyay PK, Roederer M. Seventeen-colour flow cytometry: unravelling the immune system. Nat Rev Immunol. 2004;4:648\u201355.","journal-title":"Nat Rev Immunol"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08355-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08355-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08355-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T16:04:23Z","timestamp":1767801863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-08355-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,26]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8355"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-08355-9","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,26]]},"assertion":[{"value":"19 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 November 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 December 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 December 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was conducted in accordance with the Declaration of Helsinki. Ethical approval for the research was obtained from the institutional review boards of the First Affiliated Hospital of Zhejiang University and Zhejiang University (Approval No. IIT20230513B-R1). Prior to inclusion in the study, written informed consent was obtained from all patients (or their legally authorized representatives). The case details, de-identified to protect the privacy of the patients, are used for publication. All data were handled confidentially and used solely for research purposes. No patient photo or clinical trial is involved in the study. All animal procedures were reviewed and approved by the Experimental Animal Welfare Committee of Zhejiang University (Protocol No. ZJU20230534). All experiments were carried out in compliance with the institutional guidelines of Zhejiang University and the national regulations of China for the care and use of laboratory animals. The experimental mice were raised in a certified pathogen-free facility and handled in accordance with humane practices.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"1"}}