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Mitochondrial dysfunction and oxidative stress dysregulation are core pathological mechanisms underlying DOX-induced myocardial injury. This study aimed to investigate the protective effect and underlying mechanism of Cistanche deserticola polysaccharides (CDPs) against DOX-induced cardiotoxicity in C57BL\/6J mice. Compared with the DOX model group, CDPs significantly increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), and reduced the activities of serum creatine kinase (CK), creatine kinase-MB (CK-MB), and lactate dehydrogenase (LDH). Additionally, CDPs notably decreased the malondialdehyde (MDA) levels in serum and myocardial tissue, while significantly enhancing the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Moreover, CDPs ameliorated mitochondrial swelling and crista fracture, upregulated the expression of mitochondrial respiratory chain complex-related genes, and increased adenosine triphosphate (ATP) production. In conclusion, CDPs alleviate DOX-induced cardiotoxicity and protect cardiac function by inhibiting myocardial oxidative stress and improving mitochondrial function, which provides a potential therapeutic strategy for preventing DOX-related cardiotoxicity.<\/jats:p>","DOI":"10.3390\/antiox14121461","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T15:11:24Z","timestamp":1764947484000},"page":"1461","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Cistanche deserticola Polysaccharides Protect Against Doxorubicin-Induced Cardiotoxicity via Antioxidant and Mitochondrial Mechanisms"],"prefix":"10.3390","volume":"14","author":[{"given":"Jingyi","family":"Qi","sequence":"first","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyang","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitong","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0421-0035","authenticated-orcid":false,"given":"Peng","family":"An","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7834-8742","authenticated-orcid":false,"given":"Yongting","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8987-0533","authenticated-orcid":false,"given":"Junjie","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.2174\/092986709788803312","article-title":"Doxorubicin: The Good, the Bad and the Ugly Effect","volume":"16","author":"Carvalho","year":"2009","journal-title":"Curr. 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