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Increasing evidence suggests that metabolic reprogramming, a hallmark of TNBC progression, is driven by underlying epigenetic mechanisms such as DNA methylation. The represented study performed an integrative analysis of transcriptomic (RNA-seq) and methylome data to uncover the metabolic\u2013epigenetic interplay in TNBC. Differential gene expression analysis using DESeq2 revealed significant dysregulation of key metabolic genes, including upregulation of genes encoding glycolytic and serine biosynthesis enzymes and downregulation of metabolic tumor suppressors. Genome-wide methylation profiling identified extensive cytosine\u2013phosphate\u2013guanine (CpG) hypermethylation events associated with transcriptional repression, particularly in promoter regions. Integrative analysis pinpointed a subset of metabolism-related genes exhibiting both differential expression and methylation, such as\n                    <jats:italic>FBP1<\/jats:italic>\n                    ,\n                    <jats:italic>RASSF1A<\/jats:italic>\n                    , and\n                    <jats:italic>PHGDH<\/jats:italic>\n                    . Pathway enrichment analysis highlighted aberrations in glycolysis\/gluconeogenesis, fatty acid metabolism, and one-carbon pathways (adjusted\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01). Importantly, TNBC patients with hypermethylated metabolic gene signatures displayed significantly shorter overall survival (log-rank\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.05). These findings reveal that DNA methylation-driven metabolic dysregulation contributes to TNBC aggressiveness and may provide novel biomarkers and therapeutic targets at the metabolic\u2013epigenetic interface.\n                  <\/jats:p>","DOI":"10.1186\/s43046-026-00401-7","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:53:15Z","timestamp":1788346395000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics integration uncovers epigenetic control of metabolic reprogramming in triple-negative breast cancer"],"prefix":"10.1186","volume":"38","author":[{"given":"Esraa M","family":"Hashem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai S.","family":"Mabrouk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"401_CR1","doi-asserted-by":"publisher","DOI":"10.4048\/jbc.2018.21.e41","author":"DC Temian","year":"2018","unstructured":"Temian DC, Pop LA, Irimie AI, Berindan-Neagoe I. 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Anders, \u201cModerated estimation of fold change and dispersion for RNA-seq data with DESeq2,\u201d Genome Biol, vol. 15, no. 12, Dec. 2014. https:\/\/doi.org\/10.1186\/s13059-014-0550-8.","DOI":"10.1186\/s13059-014-0550-8"}],"container-title":["Journal of the Egyptian National Cancer Institute"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43046-026-00401-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s43046-026-00401-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s43046-026-00401-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T10:53:17Z","timestamp":1788346397000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s43046-026-00401-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":67,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["401"],"URL":"https:\/\/doi.org\/10.1186\/s43046-026-00401-7","relation":{},"ISSN":["2589-0409"],"issn-type":[{"value":"2589-0409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]},"assertion":[{"value":"4 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study involved the secondary analysis of publicly available, de-identified multi-omics and clinical data obtained from The Cancer Genome Atlas Breast Invasive Carcinoma project (TCGA-BRCA). The study did not involve the direct recruitment of human participants, collection of new biological samples, or access to personally identifiable information. Therefore, additional institutional ethics approval was not required. Compliance with Regulations or Guidelines. This study was conducted in accordance with applicable ethical principles and institutional guidelines governing the secondary analysis of publicly available, de-identified human data. All data were accessed and analyzed in accordance with TCGA data-access and data-use policies. No identifiable participant information was accessed or used in this study. Ethics Approval or Waiver Statement: Ethics approval was not required for this study because it was based exclusively on the secondary analysis of publicly available, de-identified data obtained from TCGA-BRCA. No human participants were directly recruited, and no new clinical specimens or identifiable patient information were collected. Consequently, no additional approval or waiver from an institutional review board or research ethics committee was required. Informed Consent Statement: Additional informed consent was not required for this study because it used only publicly available, de-identified data from TCGA-BRCA. Informed consent and ethical approval for the original collection of the data were obtained by the institutions participating in TCGA in accordance with the applicable ethical requirements and TCGA policies.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"64"}}