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Increased pyruvate dehydrogenase kinase (PDK) enzymes in cancer cell metabolism lead to tumor resistance. This study examined dichloroacetate nanoparticles (DCA-PNPs)\/doxorubicin (Dox) impact on PDK enzymes in Ehrlich ascites carcinoma (EAC) cells. DCA-PNPs were synthesized using poly D, L-lactic-co-glycolide, polyvinyl alcohol, and characterized by encapsulation efficiency, drug-loading capacity, spectroscopy, and microscopy. Molecular docking and ADMET analysis were conducted. Seventy female CD1 mice were divided into 10 groups (n\u2009=\u20097). (Gp1) was normal negative control. Gp2 to Gp4 received DCA (50 mg\/kg), DCA-PNPs (50 mg\/kg), and Dox (0.2 mg\/kg), intraperitoneal (i.p.) injection. Gp5 to Gp10 were inoculated with EAC cells 0.5\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    \/mouse. GP5 were untreated group, served as a positive control (EAC-untreated mice or EAC-bearing mice group). GP6 to GP10 were treated with Dox, DCA, DCA-PNPs, Dox\/DCA, and Dox\/DCA-PNPs (i.p.). On day 14, tumor profile, molecular analysis, and hepatorenal alterations were assessed. Results showed DCA-PNPs size was 22.5\u2009\u00b1\u20091.72 nm, and (\u03b6) was\u2009\u2212\u20099.5 mV. Dox exhibited strongest binding affinity across PDKs (\u2212\u20097.7 to\u2009\u2212\u20098.3 kcal\/mol), while DCA showed modest affinities (\u2212\u20093.7 to\u2009\u2212\u20094.0 kcal\/mol). Dox\/DCA-PNPs treatment decreased tumor profile and hepatorenal alterations with PDKs gene suppression, increased cancer cell apoptosis and cycle arrest at G0\/G1 phase (76.1 and 64.8%). Dox\/DCA-PNPs demonstrated anti-tumor activity via inhibiting PDK enzyme.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-34562-7","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T15:26:50Z","timestamp":1769182010000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synergistic therapeutic impact of dichloroacetate nanoparticles and doxorubicin in modulating pyruvate dehydrogenase kinase in breast carcinoma model"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9108-6932","authenticated-orcid":false,"given":"Maha M.","family":"Salem","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira T.","family":"Khattab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doha M.","family":"Beltagy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai M.","family":"El-Keiy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"issue":"79","key":"34562_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.breast.2024.103851","volume":"1","author":"L Liao","year":"2025","unstructured":"Liao, L. 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