{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T23:06:22Z","timestamp":1794006382362,"version":"4.8.0"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T00:00:00Z","timestamp":1774828800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T00:00:00Z","timestamp":1778457600000},"content-version":"vor","delay-in-days":42,"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>Radioresistance is one of the primary causes of prostate cancer treatment failure and post-radiotherapy progression. However, there is currently a lack of effective targets to increase radiotherapy sensitivity and inhibit malignant progression. We identified AKR1C3 as a potential key target associated with radioresistance and malignant progression through integrated bioinformatic analysis of RNA sequencing (RNA-seq) data from prostate cancer clinical samples in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The promotion of radioresistance by AKR1C3 in both AR-positive and AR-negative prostate cancer cells was further validated through in vivo and in vitro experiments. Mechanistic studies revealed that AKR1C3 can bind to PKM2 and accelerate its degradation, thereby inhibiting glycolytic flux and enhancing oxidative phosphorylation (OXPHOS). Increased OXPHOS boosts ROS production, which further promotes NRF2 nuclear translocation, activating the transcription of DNA repair protein UBE2T. This enhanced DNA damage repair ability enables prostate cancer cells with high AKR1C3 expression to exhibit greater resistance to radiotherapy. In summary, this study reveals the molecular mechanism by which AKR1C3 is involved in metabolic reprogramming to promote radioresistance in prostate cancer through PKM2\/UBE2T. These findings indicate that targeting AKR1C3 has potential for overcoming radioresistance, providing novel insight into the clinical treatment of prostate cancer.<\/jats:p>","DOI":"10.1038\/s41419-026-08666-5","type":"journal-article","created":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T12:40:15Z","timestamp":1774874415000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["AKR1C3\u2013PKM2\u2013oxidative phosphorylation axis drives prostate cancer radioresistance via UBE2T upregulation"],"prefix":"10.1038","volume":"17","author":[{"given":"Jinyu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiongzheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binghuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruojia","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuowen","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7573-8876","authenticated-orcid":false,"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,30]]},"reference":[{"key":"8666_CR1","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.1093\/jnci\/93.22.1687","volume":"93","author":"ME Grossmann","year":"2001","unstructured":"Grossmann ME, Huang H, Tindall DJ. Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst. 2001;93:1687\u201397.","journal-title":"J Natl Cancer Inst"},{"key":"8666_CR2","first-page":"10","volume":"75","author":"RL Siegel","year":"2025","unstructured":"Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75:10\u201345.","journal-title":"CA Cancer J Clin"},{"key":"8666_CR3","unstructured":"National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 2.2024. Available from: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/prostate.pdf."},{"key":"8666_CR4","doi-asserted-by":"publisher","DOI":"10.1186\/s13148-021-01111-8","volume":"13","author":"C Macedo-Silva","year":"2021","unstructured":"Macedo-Silva C, Benedetti R, Ciardiello F, Cappabianca S, Jer\u00f3nimo C, Altucci L. Epigenetic mechanisms underlying prostate cancer radioresistance. Clin Epigenetics. 2021;13:125.","journal-title":"Clin Epigenetics"},{"key":"8666_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2023.100962","volume":"68","author":"M Cai","year":"2023","unstructured":"Cai M, Song XL, Li XA, Chen M, Guo J, Yang DH, et al. Current therapy and drug resistance in metastatic castration-resistant prostate cancer. Drug Resist Updates. 2023;68:100962.","journal-title":"Drug Resist Updates"},{"key":"8666_CR6","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1089\/ars.2013.5668","volume":"21","author":"WL Santivasi","year":"2014","unstructured":"Santivasi WL, Xia F. Ionizing radiation-induced DNA damage, response and repair. Antioxid Redox Signal. 2014;21:251\u20139.","journal-title":"Antioxid Redox Signal"},{"key":"8666_CR7","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1186\/s13046-020-01734-4","volume":"39","author":"J Sun","year":"2020","unstructured":"Sun J, Zhu Z, Li W, Shen M, Cao C, Sun Q, et al. UBE2T-regulated H2AX monoubiquitination induces hepatocellular carcinoma radioresistance by facilitating CHK1 activation. J Exp Clin Cancer Res. 2020;39:222.","journal-title":"J Exp Clin Cancer Res"},{"key":"8666_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2021.120031","volume":"286","author":"M Rajput","year":"2021","unstructured":"Rajput M, Singh R, Singh N, Singh RP. EGFR-mediated Rad51 expression potentiates intrinsic resistance in prostate cancer via EMT and DNA repair pathways. Life Sci. 2021;286:120031.","journal-title":"Life Sci"},{"key":"8666_CR9","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/sj.bjc.6605201","volume":"101","author":"C Beskow","year":"2009","unstructured":"Beskow C, Skikuniene J, Holgersson A, Nilsson B, Lewensohn R, Kanter L, et al. Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86. Br J Cancer. 2009;101:816\u201321.","journal-title":"Br J Cancer"},{"key":"8666_CR10","doi-asserted-by":"publisher","first-page":"5613","DOI":"10.1158\/1078-0432.CCR-13-1151","volume":"19","author":"M Yepuru","year":"2013","unstructured":"Yepuru M, Wu Z, Kulkarni A, Yin F, Barrett CM, Kim J, et al. Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth. Clin Cancer Res. 2013;19:5613\u201325.","journal-title":"Clin Cancer Res"},{"key":"8666_CR11","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1158\/2159-8290.CD-13-0172","volume":"3","author":"WR Polkinghorn","year":"2013","unstructured":"Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3:1245\u201353.","journal-title":"Cancer Discov"},{"key":"8666_CR12","doi-asserted-by":"publisher","first-page":"1875","DOI":"10.1158\/1535-7163.MCT-18-1322","volume":"18","author":"C Liu","year":"2019","unstructured":"Liu C, Yang JC, Armstrong CM, Lou W, Liu L, Qiu X, et al. AKR1C3 promotes AR-V7 protein stabilization and confers resistance to AR-targeted therapies in advanced prostate cancer. Mol Cancer Ther. 2019;18:1875\u201386.","journal-title":"Mol Cancer Ther"},{"key":"8666_CR13","doi-asserted-by":"publisher","first-page":"20865","DOI":"10.1074\/jbc.M115.662155","volume":"290","author":"L Fan","year":"2015","unstructured":"Fan L, Peng G, Hussain A, Fazli L, Guns E, Gleave M, et al. The steroidogenic enzyme AKR1C3 regulates stability of the ubiquitin ligase Siah2 in prostate cancer cells. J Biol Chem. 2015;290:20865\u201379.","journal-title":"J Biol Chem"},{"key":"8666_CR14","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1038\/cgt.2013.15","volume":"20","author":"L Xie","year":"2013","unstructured":"Xie L, Yu J, Guo W, Wei L, Liu Y, Wang X, et al. Aldo-keto reductase 1C3 may be a new radioresistance marker in non-small-cell lung cancer. Cancer Gene Ther. 2013;20:260\u20136.","journal-title":"Cancer Gene Ther"},{"key":"8666_CR15","doi-asserted-by":"publisher","first-page":"e111911","DOI":"10.1371\/journal.pone.0111911","volume":"9","author":"W Xiong","year":"2014","unstructured":"Xiong W, Zhao J, Yu H, Li X, Sun S, Li Y, et al. Elevated expression of AKR1C3 increases resistance of cancer cells to ionizing radiation via modulation of oxidative stress. PLoS One. 2014;9:e111911.","journal-title":"PLoS One"},{"key":"8666_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.216705","volume":"587","author":"C Uslu","year":"2024","unstructured":"Uslu C, Kapan E, Lyakhovich A. Cancer resistance and metastasis are maintained through oxidative phosphorylation. Cancer Lett. 2024;587:216705.","journal-title":"Cancer Lett"},{"key":"8666_CR17","doi-asserted-by":"crossref","unstructured":"Chen D, Barsoumian HB, Fischer G, Yang L, Verma V, Younes AI, et al. Combination treatment with radiotherapy and a novel oxidative phosphorylation inhibitor overcomes PD-1 resistance and enhances antitumor immunity. J Immunother Cancer. Available from: https:\/\/jitc.bmj.com\/content\/8\/1\/e000289.","DOI":"10.1136\/jitc-2019-000289"},{"key":"8666_CR18","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1038\/bjc.2016.152","volume":"114","author":"P Sancho","year":"2016","unstructured":"Sancho P, Barneda D, Heeschen C. Hallmarks of cancer stem cell metabolism. Br J Cancer. 2016;114:1305\u201312.","journal-title":"Br J Cancer"},{"key":"8666_CR19","doi-asserted-by":"publisher","first-page":"2970","DOI":"10.1158\/1078-0432.CCR-20-3913","volume":"27","author":"DF Boreel","year":"2021","unstructured":"Boreel DF, Span PN, Heskamp S, Adema GJ, Bussink J. Targeting oxidative phosphorylation to increase the efficacy of radio- and immune-combination therapy. Clin Cancer Res. 2021;27:2970\u20138.","journal-title":"Clin Cancer Res"},{"key":"8666_CR20","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1093\/neuonc\/noae255","volume":"27","author":"H Shen","year":"2025","unstructured":"Shen H, Mudassar F, Ma S, Wang X, Nguyen S, Bal N, et al. Inhibition of mitochondrial bioenergetics and hypoxia to radiosensitize diffuse intrinsic pontine glioma. Neuro Oncol. 2025;27:1061\u201375.","journal-title":"Neuro Oncol"},{"key":"8666_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-00183-z","volume":"11","author":"T \u00d6zg\u00fcm\u00fc\u015f","year":"2021","unstructured":"\u00d6zg\u00fcm\u00fc\u015f T, Sulaieva O, Jessen LE, Jain R, Falhammar H, Nystr\u00f6m T, et al. Reduced expression of OXPHOS and DNA damage genes is linked to protection from microvascular complications in long-term type 1 diabetes: the PROLONG study. Sci Rep. 2021;11:20735.","journal-title":"Sci Rep"},{"key":"8666_CR22","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.canlet.2020.12.010","volume":"503","author":"E Abad","year":"2021","unstructured":"Abad E, Samino S, Grodzicki RL, Pagano G, Trifuoggi M, Graifer D, et al. Identification of metabolic changes leading to cancer susceptibility in Fanconi anemia cells. Cancer Lett. 2021;503:185\u201396.","journal-title":"Cancer Lett"},{"key":"8666_CR23","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202401394","volume":"11","author":"Z Zhou","year":"2024","unstructured":"Zhou Z, Jiang X, Yi L, Li C, Wang H, Xiong W, et al. Mitochondria energy metabolism depression as a novel adjuvant to sensitize radiotherapy and inhibit radiation-induced pulmonary fibrosis. Adv Sci. 2024;11:e2401394.","journal-title":"Adv Sci"},{"key":"8666_CR24","doi-asserted-by":"publisher","first-page":"4491","DOI":"10.3390\/ijms23094491","volume":"23","author":"V Firlej","year":"2022","unstructured":"Firlej V, Soyeux P, Nourieh M, Huet E, Semprez F, Allory Y, et al. Overexpression of nucleolin and associated genes in prostate cancer. Int J Mol Sci. 2022;23:4491.","journal-title":"Int J Mol Sci"},{"key":"8666_CR25","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","volume":"43","author":"ME Ritchie","year":"2015","unstructured":"Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:e47.","journal-title":"Nucleic Acids Res"},{"key":"8666_CR26","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1038\/75556","volume":"25","author":"M Ashburner","year":"2000","unstructured":"Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, et al. Gene ontology: a tool for the unification of biology. The Gene Ontology Consortium. Nat Genet. 2000;25:25\u20139.","journal-title":"Nat Genet"},{"key":"8666_CR27","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","volume":"28","author":"M Kanehisa","year":"2000","unstructured":"Kanehisa M, Goto S. KEGG: Kyoto Encyclopedia of Genes and genomes. Nucleic Acids Res. 2000;28:27\u201330.","journal-title":"Nucleic Acids Res"},{"key":"8666_CR28","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","volume":"16","author":"G Yu","year":"2012","unstructured":"Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284\u20137.","journal-title":"OMICS"},{"key":"8666_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7","volume":"14","author":"S H\u00e4nzelmann","year":"2013","unstructured":"H\u00e4nzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinforma. 2013;14:7.","journal-title":"BMC Bioinforma"},{"key":"8666_CR30","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.canlet.2020.06.005","volume":"494","author":"H Yin","year":"2020","unstructured":"Yin H, Wang X, Zhang X, Zeng Y, Xu Q, Wang W, et al. UBE2T promotes radiation resistance in non-small cell lung cancer via inducing epithelial-mesenchymal transition and the ubiquitination-mediated FOXO1 degradation. Cancer Lett. 2020;494:121\u201331.","journal-title":"Cancer Lett"},{"key":"8666_CR31","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/S0960-0760(99)00038-2","volume":"69","author":"TM Penning","year":"1999","unstructured":"Penning TM. Molecular determinants of steroid recognition and catalysis in aldo-keto reductases. Lessons from 3\u03b1-hydroxysteroid dehydrogenase. J Steroid Biochem Mol Biol. 1999;69:211\u201325.","journal-title":"J Steroid Biochem Mol Biol"},{"key":"8666_CR32","doi-asserted-by":"crossref","unstructured":"Yu X, Yan J, Li Y, Cheng J, Zheng L, Fu T, et al. Inhibition of castration-resistant prostate cancer growth by genistein through suppression of AKR1C3. Food Nutr Res. 2023;31:67.","DOI":"10.29219\/fnr.v67.9024"},{"key":"8666_CR33","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1007\/s10637-014-0130-5","volume":"32","author":"A Kikuchi","year":"2014","unstructured":"Kikuchi A, Furutani T, Azami H, Watanabe K, Niimi T, Kamiyama Y, et al. In vitro and in vivo characterisation of ASP9521: a novel, selective orally bioavailable inhibitor of 17\u03b2-hydroxysteroid dehydrogenase type 5 (17\u03b2HSD5; AKR1C3). Investig N Drugs. 2014;32:860\u201370.","journal-title":"Investig N Drugs"},{"key":"8666_CR34","doi-asserted-by":"publisher","first-page":"1222","DOI":"10.1158\/2159-8290.CD-13-0679","volume":"3","author":"J Bartek","year":"2013","unstructured":"Bartek J, Mistrik M, Bartkova J. Androgen receptor signaling fuels DNA repair and radioresistance in prostate cancer. Cancer Discov. 2013;3:1222\u20134.","journal-title":"Cancer Discov"},{"key":"8666_CR35","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.tem.2010.01.002","volume":"21","author":"KE Knudsen","year":"2010","unstructured":"Knudsen KE, Penning TM. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol Metab. 2010;21:315\u201324.","journal-title":"Trends Endocrinol Metab"},{"key":"8666_CR36","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1016\/j.mce.2005.12.009","volume":"248","author":"TM Penning","year":"2006","unstructured":"Penning TM, Steckelbroeck S, Bauman DR, Miller MW, Jin Y, Peehl DM, et al. Aldo-keto reductase (AKR) 1C3: Role in prostate disease and the development of specific inhibitors. Mol Cell Endocrinol. 2006;248:182\u201391.","journal-title":"Mol Cell Endocrinol"},{"key":"8666_CR37","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","volume":"41","author":"MV Liberti","year":"2016","unstructured":"Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41:211\u20138.","journal-title":"Trends Biochem Sci"},{"key":"8666_CR38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2025.148067","volume":"330","author":"Zulfareen","year":"2025","unstructured":"Zulfareen, Taiyab A, Hasan GM, Hassan MdI. A review on the role of pyruvate kinase M2 in cancer: from metabolic switch to transcriptional regulation. Int J Biol Macromol. 2025;330:148067.","journal-title":"Int J Biol Macromol."},{"key":"8666_CR39","doi-asserted-by":"publisher","first-page":"330","DOI":"10.3109\/07357907.2014.919306","volume":"32","author":"N Wong","year":"2014","unstructured":"Wong N, Yan J, Ojo D, De Melo J, Cutz JC, Tang D. Changes in PKM2 associate with prostate cancer progression. Cancer Investig. 2014;32:330\u20138.","journal-title":"Cancer Investig"},{"key":"8666_CR40","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.cmet.2014.12.005","volume":"21","author":"EM Palsson-McDermott","year":"2015","unstructured":"Palsson-McDermott EM, Curtis AM, Goel G, Lauterbach MAR, Sheedy FJ, Gleeson LE, et al. Pyruvate kinase M2 regulates Hif-1\u03b1 activity and IL-1\u03b2 induction and is a critical determinant of the warburg effect in LPS-activated macrophages. Cell Metab. 2015;21:65\u201380.","journal-title":"Cell Metab"},{"key":"8666_CR41","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41388-018-0414-x","volume":"38","author":"HJ Wang","year":"2019","unstructured":"Wang HJ, Pochampalli M, Wang LY, Zou JX, Li PS, Hsu SC, et al. KDM8\/JMJD5, as a dual coactivator of AR and PKM2, integrates the AR\/EZH2 network and tumor metabolism in CRPC. Oncogene. 2019;38:17\u201332.","journal-title":"Oncogene"},{"key":"8666_CR42","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1186\/s13578-019-0317-8","volume":"9","author":"Z Zhang","year":"2019","unstructured":"Zhang Z, Deng X, Liu Y, Liu Y, Sun L, Chen F. PKM2, function, expression and regulation. Cell Biosci. 2019;9:52.","journal-title":"Cell Biosci"},{"key":"8666_CR43","doi-asserted-by":"publisher","first-page":"168","DOI":"10.3390\/biom15020168","volume":"15","author":"W Ma","year":"2025","unstructured":"Ma W, Zhou S. Metabolic rewiring in the face of genomic assault: integrating DNA damage response and cellular metabolism. Biomolecules. 2025;15:168.","journal-title":"Biomolecules"},{"key":"8666_CR44","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","volume":"66","author":"AN Blackford","year":"2017","unstructured":"Blackford AN, Jackson SP. ATM, ATR and DNA-PK: the trinity at the heart of the DNA damage response. Mol Cell. 2017;66:801\u201317.","journal-title":"Mol Cell"},{"key":"8666_CR45","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/nrm.2017.48","volume":"18","author":"HHY Chang","year":"2017","unstructured":"Chang HHY, Pannunzio NR, Adachi N, Lieber MR. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol. 2017;18:495\u2013506.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"8666_CR46","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2018.101084","volume":"25","author":"US Srinivas","year":"2019","unstructured":"Srinivas US, Tan BWQ, Vellayappan BA, Jeyasekharan AD. ROS and the DNA damage response in cancer. Redox Biol. 2019;25:101084.","journal-title":"Redox Biol"},{"key":"8666_CR47","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1642100","volume":"15","author":"S Yang","year":"2025","unstructured":"Yang S, Li Y, Zhang J, Shen A, Hu B, Yan J. The interplay between DNA damage response and mitochondrial dysfunction in radiotherapy. Front Oncol. 2025;15:1642100.","journal-title":"Front Oncol"},{"key":"8666_CR48","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.freeradbiomed.2017.03.030","volume":"107","author":"J Cadet","year":"2017","unstructured":"Cadet J, Davies KJA. Oxidative DNA damage & repair: an introduction. Free Radic Biol Med. 2017;107:2\u201312.","journal-title":"Free Radic Biol Med"},{"key":"8666_CR49","doi-asserted-by":"publisher","first-page":"218","DOI":"10.31083\/j.fbl2906218","volume":"29","author":"AP Gureev","year":"2024","unstructured":"Gureev AP, Chernyshova EV, Krutskikh EP, Sadovnikova IS, Tekutskaya EE, Dorohova AA. Role of the Nrf2\/ARE pathway in the mtDNA reparation. Front Biosci. 2024;29:218.","journal-title":"Front Biosci"},{"key":"8666_CR50","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.radonc.2011.05.059","volume":"101","author":"CHMA Ramaekers","year":"2011","unstructured":"Ramaekers CHMA, van den Beucken T, Meng A, Kassam S, Thoms J, Bristow RG, et al. Hypoxia disrupts the Fanconi anemia pathway and sensitizes cells to chemotherapy through regulation of UBE2T. Radiother Oncol. 2011;101:190\u20137.","journal-title":"Radiother Oncol"},{"key":"8666_CR51","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s13046-020-01724-6","volume":"39","author":"F Mudassar","year":"2020","unstructured":"Mudassar F, Shen H, O\u2019Neill G, Hau E. Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas. J Exp Clin Cancer Res. 2020;39:208.","journal-title":"J Exp Clin Cancer Res"},{"key":"8666_CR52","doi-asserted-by":"publisher","first-page":"6741","DOI":"10.1158\/1078-0432.CCR-13-1787","volume":"19","author":"VE Zannella","year":"2013","unstructured":"Zannella VE, Dal Pra A, Muaddi H, McKee TD, Stapleton S, Sykes J, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res. 2013;19:6741\u201350.","journal-title":"Clin Cancer Res"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08666-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08666-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08666-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T11:03:14Z","timestamp":1778497394000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-026-08666-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,30]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8666"],"URL":"https:\/\/doi.org\/10.1038\/s41419-026-08666-5","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,30]]},"assertion":[{"value":"3 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2026","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 March 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2026","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":"All authors have read and approved the final manuscript and consent to its publication.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All animal experiments conducted in this study were approved by the Ethics Committee of the College of Pharmacy, Beihua University (Approval No. 2024082301). All animal experiments were performed in accordance with relevant guidelines and regulations.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"433"}}