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Increasing research suggests that lysine lactylation (KLA) and DNA damage repair (DDR) play critical roles in tumor progression and that KLA and DDR are interconnected, as KLA can modulate DDR protein function, thereby influencing genome stability and drug response, while DDR signaling can reciprocally reshape lactate metabolism and KLA activity. In this study, we developed a novel prognostic gene signature (KLA and DDR index, KLDRI) based on KLA- and DDR-related genes. Model genes (PGK1, MORF4L2, RAD54B, RPA3, CCND2) were generated via LASSO-Cox regression. Patients were stratified into high- and low-risk groups according to KLDRI, the robust prognostic value of which was demonstrated via survival and validation analyses in the TCGA cohort and the METABRIC and GSE96058 cohorts, respectively. Tumor microenvironment analysis indicated an immunologically suppressed phenotype in high-risk patients, whereas low-risk patients exhibited an immune-inflamed microenvironment. Drug sensitivity analysis indicated reduced sensitivity to multiple chemotherapy and targeted therapy drugs in the high-risk group. Single-cell transcriptomic analysis revealed differential gene expression patterns between risk groups. A prognostic nomogram based on KLDRI was developed to predict overall survival. Furthermore, functional experiments demonstrated that RPA3 knockdown suppressed cancer cell proliferation and migration, sensitized cells to cisplatin treatment, and reduced global lactylation, which may serve as a novel biomarker and potential therapeutic target. These findings enhance our understanding of the interplay between KLA, DDR, and breast cancer progression, facilitating the development of personalized therapeutic strategies.<\/jats:p>","DOI":"10.3390\/ijms27104493","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T14:40:31Z","timestamp":1779115231000},"page":"4493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Construction of a Lysine Lactylation- and DNA Damage Repair-Related Gene Signature to Predict the Prognosis and Drug Sensitivity of Breast Cancer Patients"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4166-4008","authenticated-orcid":false,"given":"Liang","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenwei","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaorong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luoqi","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinxuan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2129-7443","authenticated-orcid":false,"given":"Wenjin","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3874-9108","authenticated-orcid":false,"given":"Jinsong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1002\/ijc.35278","article-title":"The GLOBOCAN 2022 Cancer Estimates: Data Sources, Methods, and a Snapshot of the Cancer Burden Worldwide","volume":"156","author":"Filho","year":"2024","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1093\/jnci\/djab202","article-title":"The Incidence of Breast Cancer Recurrence 10\u201332 Years After Primary Diagnosis","volume":"114","author":"Pedersen","year":"2022","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/nrc3038","article-title":"Otto Warburg\u2019s Contributions to Current Concepts of Cancer Metabolism","volume":"11","author":"Koppenol","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/s41586-024-07620-9","article-title":"NBS1 Lactylation Is Required for Efficient DNA Repair and Chemotherapy Resistance","volume":"631","author":"Chen","year":"2024","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41577-020-0406-2","article-title":"Lactate Modulation of Immune Responses in Inflammatory versus Tumour Microenvironments","volume":"21","author":"Certo","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic Regulation of Gene Expression by Histone Lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1016\/j.ccell.2024.09.006","article-title":"Lactylation in Cancer: Current Understanding and Challenges","volume":"42","author":"Li","year":"2024","journal-title":"Cancer Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s12276-025-01410-7","article-title":"Protein Lactylation in Cancer: Mechanisms and Potential Therapeutic Implications","volume":"57","author":"Rho","year":"2025","journal-title":"Exp. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1038\/s41590-024-01985-9","article-title":"Histone Lactylation Drives CD8+ T Cell Metabolism and Function","volume":"25","author":"Raychaudhuri","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/s12943-024-02008-9","article-title":"Positive Feedback Regulation between Glycolysis and Histone Lactylation Drives Oncogenesis in Pancreatic Ductal Adenocarcinoma","volume":"23","author":"Li","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4219","DOI":"10.1093\/eurheartj\/ehae379","article-title":"TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation","volume":"45","author":"Li","year":"2024","journal-title":"Eur. Heart J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/s41392-023-01605-2","article-title":"STAT5 Promotes PD-L1 Expression by Facilitating Histone Lactylation to Drive Immunosuppression in Acute Myeloid Leukemia","volume":"8","author":"Huang","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s12943-025-02295-w","article-title":"Lactate Accumulation Induces H4K12la to Activate Super-Enhancer-Driven RAD23A Expression and Promote Niraparib Resistance in Ovarian Cancer","volume":"24","author":"Lu","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hou, X., Ouyang, J., Tang, L., Wu, P., Deng, X., Yan, Q., Shi, L., Fan, S., Fan, C., and Guo, C. (2024). KCNK1 Promotes Proliferation and Metastasis of Breast Cancer Cells by Activating Lactate Dehydrogenase A (LDHA) and up-Regulating H3K18 Lactylation. PLoS Biol., 22.","DOI":"10.1371\/journal.pbio.3002666"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.cell.2023.11.022","article-title":"Metabolic Regulation of Homologous Recombination Repair by MRE11 Lactylation","volume":"187","author":"Chen","year":"2024","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1016\/j.cmet.2024.07.011","article-title":"Glycometabolic Reprogramming-Induced XRCC1 Lactylation Confers Therapeutic Resistance in ALDH1A3-Overexpressing Glioblastoma","volume":"36","author":"Li","year":"2024","journal-title":"Cell Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3055","DOI":"10.7150\/thno.104858","article-title":"Targeting Platinum-Resistant Ovarian Cancer by Disrupting Histone and RAD51 Lactylation","volume":"15","author":"Sun","year":"2025","journal-title":"Theranostics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.cell.2017.01.002","article-title":"Endogenous DNA Damage as a Source of Genomic Instability in Cancer","volume":"168","author":"Tubbs","year":"2017","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1016\/j.molcel.2025.06.019","article-title":"Lactylation of XLF Promotes Non-Homologous End-Joining Repair and Chemoresistance in Cancer","volume":"85","author":"Jin","year":"2025","journal-title":"Mol. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chang, Y., Huang, Z., Quan, H., Li, H., Yang, S., Song, Y., Wang, J., Yuan, J., and Wu, C. (2022). Construction of a DNA Damage Repair Gene Signature for Predicting Prognosis and Immune Response in Breast Cancer. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.1085632"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Min, S., Zhang, X., Liu, Y., Wang, W., Guan, J., Chen, Y., Sun, M., Wang, Z., and Wang, T. (2025). Personalized Treatment Decision-Making Using a Machine Learning-Derived Lactylation Signature for Breast Cancer Prognosis. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1540018"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/s41420-024-01898-4","article-title":"Histone Lactylation Promotes Malignant Progression by Facilitating USP39 Expression to Target PI3K\/AKT\/HIF-1\u03b1 Signal Pathway in Endometrial Carcinoma","volume":"10","author":"Wei","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1016\/j.ymthe.2021.04.036","article-title":"FOXO3A-Induced LINC00926 Suppresses Breast Tumor Growth and Metastasis through Inhibition of PGK1-Mediated Warburg Effect","volume":"29","author":"Chu","year":"2021","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6915","DOI":"10.1038\/s41467-024-51232-w","article-title":"Hypoxia-Induced Downregulation of PGK1 Crotonylation Promotes Tumorigenesis by Coordinating Glycolysis and the TCA Cycle","volume":"15","author":"Guo","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100253","DOI":"10.1016\/j.mcpro.2022.100253","article-title":"MRG Proteins Are Shared by Multiple Protein Complexes With Distinct Functions","volume":"21","author":"Devoucoux","year":"2022","journal-title":"Mol. Cell. Proteom. MCP"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40364-024-00719-1","article-title":"MORF4L2 Induces Immunosuppressive Microenvironment and Immunotherapy Resistance through GRHL2\/MORF4L2\/H4K12Ac\/CSF1 Axis in Triple-Negative Breast Cancer","volume":"13","author":"Sui","year":"2025","journal-title":"Biomark. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1093\/nar\/30.6.1346","article-title":"Human Rad54B Is a Double-Stranded DNA-Dependent ATPase and Has Biochemical Properties Different from Its Structural Homolog in Yeast, Tid1\/Rdh54","volume":"30","author":"Tanaka","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"109341","DOI":"10.1016\/j.biopha.2019.109341","article-title":"RAD54B Potentiates Tumor Growth and Predicts Poor Prognosis of Patients with Luminal A Breast Cancer","volume":"118","author":"Zhang","year":"2019","journal-title":"Biomed. Pharmacother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e2014622","DOI":"10.1001\/jamanetworkopen.2020.14622","article-title":"Prediction of Overall Survival Among Female Patients With Breast Cancer Using a Prognostic Signature Based on 8 DNA Repair-Related Genes","volume":"3","author":"Zhang","year":"2020","journal-title":"JAMA Netw. Open"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1097\/CM9.0000000000001328","article-title":"Notoginsenoside R1 Attenuates Breast Cancer Progression by Targeting CCND2 and YBX3","volume":"134","author":"Qin","year":"2021","journal-title":"Chin. Med. J."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hung, C.-S., Wang, S.-C., Yen, Y.-T., Lee, T.-H., Wen, W.-C., and Lin, R.-K. (2018). Hypermethylation of CCND2 in Lung and Breast Cancer Is a Potential Biomarker and Drug Target. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103096"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.trecan.2020.01.007","article-title":"TP53 Mutations and Outcomes in Breast Cancer: Reading beyond the Headlines","volume":"6","author":"Shahbandi","year":"2020","journal-title":"Trends Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1016\/j.cell.2024.04.002","article-title":"Alanyl-tRNA Synthetase, AARS1, Is a Lactate Sensor and Lactyltransferase That Lactylates P53 and Contributes to Tumorigenesis","volume":"187","author":"Zong","year":"2024","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/s41392-023-01452-1","article-title":"Macrophages in Immunoregulation and Therapeutics","volume":"8","author":"Chen","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2250","DOI":"10.1016\/j.apsb.2023.02.001","article-title":"Entinostat, a Class I Selective Histone Deacetylase Inhibitor, plus Exemestane for Chinese Patients with Hormone Receptor-Positive Advanced Breast Cancer: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial","volume":"13","author":"Xu","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1002\/ddr.21978","article-title":"Knockdown of Replication Protein A 3 Induces Protective Autophagy and Enhances Cisplatin Sensitivity in Lung Adenocarcinoma by Inhibiting AKT\/mTOR Signaling via Binding to Cyclin-Dependent Kinases Regulatory Subunit 2","volume":"83","author":"Chen","year":"2022","journal-title":"Drug Dev. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2872","DOI":"10.1111\/jcmm.13200","article-title":"RPA3 Is a Potential Marker of Prognosis and Radioresistance for Nasopharyngeal Carcinoma","volume":"21","author":"Qu","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/s41419-025-08113-x","article-title":"HAT1 Functions as a Lactyltransferase and Mediates RPA1 Lactylation to Promote DNA Repair and Radioresistance in Lung Adenocarcinoma","volume":"16","author":"He","year":"2025","journal-title":"Cell Death Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5165","DOI":"10.1158\/0008-5472.CAN-14-0306","article-title":"RPA Inhibition Increases Replication Stress and Suppresses Tumor Growth","volume":"74","author":"Glanzer","year":"2014","journal-title":"Cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Alanazi, I.M., Abo Nahas, H.H., Mohamed, D.I., Hosny, N., Elewa, Y.H.A., Agarwal, M., Ibrahim, I.A.A., Falemban, A.H., Bamagous, G.A., and Sindi, E.R. (2025). Integrative Metabolomic, Network Pharmacology, and Experimental Evidence for Lepidium Sativum Seed Extract as a Natural Modulator of Pulmonary Fibrosis via the ncNRFR\/Let-7d Regulatory Pathway. Pharmaceuticals, 18.","DOI":"10.3390\/ph18121820"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.2147\/DDDT.S463626","article-title":"Trimetazidine Alleviates Bleomycin-Induced Pulmonary Fibrosis by Targeting the Long Noncoding RNA CBR3-AS1-Mediated miRNA-29 and Resistin-Like Molecule Alpha 1: Deciphering a Novel Trifecta Role of LncRNA CBR3-AS1\/miRNA-29\/FIZZ1 Axis in Lung Fibrosis","volume":"18","author":"Alzahrani","year":"2024","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Mohamed, D.I., Abo Nahas, H.H., Elshaer, A.M., El-Waseef, D.A.E.-D.A., El-Kharashi, O.A., Mohamed, S.M.Y., Sabry, Y.G., Almaimani, R.A., Almasmoum, H.A., and Altamimi, A.S. (2023). Unveiling the Interplay between NSAID-Induced Dysbiosis and Autoimmune Liver Disease in Children: Insights into the Hidden Gateway to Autism Spectrum Disorders. Evidence from Ex Vivo, in Vivo, and Clinical Studies. Front. Cell. Neurosci., 17.","DOI":"10.3389\/fncel.2023.1268126"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4493\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T04:26:01Z","timestamp":1779164761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4493"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,17]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104493"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104493","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,17]]}}}