{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:42:13Z","timestamp":1785436933775,"version":"3.56.0"},"reference-count":34,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Heilongjiang Provincial Natural Science Outstanding Youth Fund Project","award":["YQ2024H001"],"award-info":[{"award-number":["YQ2024H001"]}]},{"name":"Jiamusi University National Fund Cultivation Project","award":["JMSUGPZR2022-013"],"award-info":[{"award-number":["JMSUGPZR2022-013"]}]},{"award":["JMSUGPZR2022-013"],"award-info":[{"award-number":["JMSUGPZR2022-013"]}],"id":[{"id":"https:\/\/ror.org\/01vasff55","id-type":"ROR","asserted-by":"publisher"}]},{"name":"College Student Innovation and Entrepreneurship Training Program","award":["202410222001"],"award-info":[{"award-number":["202410222001"]}]},{"name":"Jiamusi University National Cultivation Project","award":["JMSUGPZR2210"],"award-info":[{"award-number":["JMSUGPZR2210"]}]},{"award":["JMSUGPZR2210"],"award-info":[{"award-number":["JMSUGPZR2210"]}],"id":[{"id":"https:\/\/ror.org\/01vasff55","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Breast cancer (BRCA) is the most common cancer worldwide, with an incidence exceeding that of lung cancer. Protein lactylation, a newly identified post-translational modification involving the binding of lactic acid to lysine residues, plays an important role in BRCA. However, its role in BRCA progression remains largely unexplored. This study aims to identify and characterize the lactylation-related genes involved in BRCA biology. Transcriptomic and clinical data of BRCA and normal breast tissues were obtained from TCGA and GEO. Lactylation-related genes were curated from literature and intersected with BRCA datasets to identify candidates. A prognostic risk model was constructed using LASSO and Cox regression. Functional enrichment was performed using KEGG, GSVA, and GSEA. Immune correlations were evaluated by ESTIMATE, CIBERSORT. Single-cell RNA-seq data were integrated to assess gene expression heterogeneity across tumor and immune compartments. In vitro, MDA-MB-231 cells were treated with sodium L-lactate and lactylation-inducing agents, and gene expression was validated by Western blot and RT-qPCR, while EdU and wound healing assays evaluated proliferation and migration. We identified six hub genes associated with the immune microenvironment. Notably, S100A4 is significantly underexpressed, suggesting their potential regulatory roles in BRCA. Further analysis demonstrated that lactylation-related genes are closely linked to immune regulation in BRCA, indicating a possible crosstalk between metabolic modification and tumor immunity. Additionally, we found that lactylation significantly influences gene expression patterns and immune infiltration in BRCA. Importantly, lactic acid ions were shown to upregulate lactylation levels in BRCA cells, underscoring the functional impact of metabolic signals on post-translational modifications in tumorigenesis. Our findings indicate a potential mechanism wherein lactylation affects BRCA progression via lactic acid-driven regulation of the immune microenvironment; they also highlight the possible involvement of S100A4 in this process and offer new insights that could contribute to the diagnosis and treatment of BRCA.<\/jats:p>","DOI":"10.3390\/cimb48040416","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:30:36Z","timestamp":1776443436000},"page":"416","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Key Genes Regulated by Lactylation Modification and Associated with Tumor Immune Microenvironment in Breast Cancer"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4782-9967","authenticated-orcid":false,"given":"Yaohong","family":"Xie","sequence":"first","affiliation":[{"name":"Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Ge","sequence":"additional","affiliation":[{"name":"Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Miao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengxia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Xia","sequence":"additional","affiliation":[{"name":"Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi 154007, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40659-017-0140-9","article-title":"Awareness and Current Knowledge of Breast Cancer","volume":"50","author":"Akram","year":"2017","journal-title":"Biol. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1038\/s41591-025-03502-3","article-title":"Global Patterns and Trends in Breast Cancer Incidence and Mortality across 185 Countries","volume":"31","author":"Kim","year":"2025","journal-title":"Nat. Med."},{"key":"ref_3","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_4","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_5","doi-asserted-by":"crossref","unstructured":"Chen, L., Huang, L., Gu, Y., Cang, W., Sun, P., and Xiang, Y. (2022). Lactate-Lactylation Hands between Metabolic Reprogramming and Immunosuppression. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911943"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Li, S., Chang, M., Tong, L., Wang, Y., Wang, M., and Wang, F. (2023). Screening Potential lncRNA Biomarkers for Breast Cancer and Colorectal Cancer Combining Random Walk and Logistic Matrix Factorization. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.1023615"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Liu, X., Zhang, Y., Li, W., and Zhou, X. (2022). Lactylation, an Emerging Hallmark of Metabolic Reprogramming: Current Progress and Open Challenges. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.972020"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.semcancer.2019.08.012","article-title":"Metastatic Heterogeneity of Breast Cancer: Molecular Mechanism and Potential Therapeutic Targets","volume":"60","author":"Liang","year":"2020","journal-title":"Semin. Cancer Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e50663","DOI":"10.7554\/eLife.50663","article-title":"Lactate-Mediated Epigenetic Reprogramming Regulates Formation of Human Pancreatic Cancer-Associated Fibroblasts","volume":"8","author":"Bhagat","year":"2019","journal-title":"eLife"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"107205","DOI":"10.1016\/j.phrs.2024.107205","article-title":"Epigenetic Modulations in Triple-Negative Breast Cancer: Therapeutic Implications for Tumor Microenvironment","volume":"204","author":"Zhou","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s12943-024-01990-4","article-title":"Modulation of the Tumor Microenvironment and Mechanism of Immunotherapy-Based Drug Resistance in Breast Cancer","volume":"23","author":"Kundu","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"bqab088","DOI":"10.1210\/endocr\/bqab088","article-title":"Control of Breast Cancer Pathogenesis by Histone Methylation and the Hairless Histone Demethylase","volume":"162","author":"Trager","year":"2021","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13046-024-02943-x","article-title":"Lactylation Stabilizes DCBLD1 Activating the Pentose Phosphate Pathway to Promote Cervical Cancer Progression","volume":"43","author":"Meng","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s12943-023-01856-1","article-title":"CircXRN2 Suppresses Tumor Progression Driven by Histone Lactylation through Activating the Hippo Pathway in Human Bladder Cancer","volume":"22","author":"Xie","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"2003049","DOI":"10.1002\/advs.202003049","article-title":"Modeling Heterogeneity of Triple-negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance","volume":"8","author":"Lamballe","year":"2021","journal-title":"Adv. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wu, Q., Cao, H., Jin, J., Ma, D., Niu, Y., Yu, Y., Wang, X., and Xia, Y. (2025). Integrated Multi-Omics Analysis Reveals the Functional and Prognostic Significance of Lactylation-Related Gene PRDX1 in Breast Cancer. Front. Mol. Biosci., 12.","DOI":"10.3389\/fmolb.2025.1580622"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Deng, J., and Liao, X. (2023). Lysine Lactylation (Kla) Might Be a Novel Therapeutic Target for Breast Cancer. BMC Med. Genomics, 16.","DOI":"10.1186\/s12920-023-01726-1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Liu, H., Pan, M., Liu, M., Zeng, L., Li, Y., Huang, Z., Guo, C., and Wang, H. (2024). Lactate: A Rising Star in Tumors and Inflammation. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1496390"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"103194","DOI":"10.1016\/j.redox.2024.103194","article-title":"Histone Lactylation-Regulated METTL3 Promotes Ferroptosis via m6A-Modification on ACSL4 in Sepsis-Associated Lung Injury","volume":"74","author":"Wu","year":"2024","journal-title":"Redox Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wei, Y., Guo, H., Chen, S., and Tang, X.X. (2024). Regulation of Macrophage Activation by Lactylation in Lung Disease. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1427739"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Dias Nunes, J., Demeestere, I., and Devos, M. (2023). BRCA Mutations and Fertility Preservation. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010204"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Kocianova, E., Piatrikova, V., and Golias, T. (2022). Revisiting the Warburg Effect with Focus on Lactate. Cancers, 14.","DOI":"10.3390\/cancers14246028"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6124","DOI":"10.1002\/cam4.1820","article-title":"Lactate Dehydrogenase a: A Key Player in Carcinogenesis and Potential Target in Cancer Therapy","volume":"7","author":"Feng","year":"2018","journal-title":"Cancer Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s12967-024-04955-9","article-title":"A Multi-Dimensional Approach to Unravel the Intricacies of Lactylation Related Signature for Prognostic and Therapeutic Insight in Colorectal Cancer","volume":"22","author":"Huang","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e24777","DOI":"10.1016\/j.heliyon.2024.e24777","article-title":"Lactylation-Related Gene Signature for Prognostic Prediction and Immune Infiltration Analysis in Breast Cancer","volume":"10","author":"Jiao","year":"2024","journal-title":"Heliyon"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1021\/acs.jproteome.9b00085","article-title":"Optimized Cross-Linking Mass Spectrometry for in Situ Interaction Proteomics","volume":"18","author":"Ser","year":"2019","journal-title":"J. Proteome Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1038\/s41598-018-37796-w","article-title":"Cytotoxicity of Eupatorin in MCF-7 and MDA-MB-231 Human Breast Cancer Cells via Cell Cycle Arrest, Anti-Angiogenesis and Induction of Apoptosis","volume":"9","author":"Razak","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.canlet.2017.09.052","article-title":"CNOT2 Promotes Proliferation and Angiogenesis via VEGF Signaling in MDA-MB-231 Breast Cancer Cells","volume":"412","author":"Sohn","year":"2018","journal-title":"Cancer Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg Effect: How Does It Benefit Cancer Cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.drup.2018.03.001","article-title":"How the Warburg Effect Supports Aggressiveness and Drug Resistance of Cancer Cells?","volume":"38","author":"Icard","year":"2018","journal-title":"Drug Resist. Updat."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e151601","DOI":"10.1172\/JCI151601","article-title":"HMGA1 induces FGF19 to drive pancreatic carcinogenesis and stroma formation","volume":"133","author":"Chia","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.cyto.2014.12.001","article-title":"Hepatocarcinoma cell-derived hepatoma-derived growth factor (HDGF) induces regulatory T cells","volume":"72","author":"Sun","year":"2015","journal-title":"Cytokine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1433393","DOI":"10.3389\/fimmu.2024.1433393","article-title":"Lactylation signature identifies liver fibrosis phenotypes and traces fibrotic progression to hepatocellular carcinoma","volume":"15","author":"Li","year":"2024","journal-title":"Front. Immunol."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/4\/416\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T10:40:31Z","timestamp":1776681631000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/4\/416"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,17]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["cimb48040416"],"URL":"https:\/\/doi.org\/10.3390\/cimb48040416","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,17]]}}}