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Although Chinese yam polysaccharides (CYPs), the primary bioactive macromolecules isolated from Dioscorea opposita Thunb, exhibit well-documented antioxidant and anti-inflammatory properties, their cardioprotective efficacy against acute I\/R injury and the underlying multiscale mechanisms remain unexplored. This study investigated the protective effects of CYPs using an in vivo mouse model of myocardial I\/R injury. Methods: An in vivo mouse model of myocardial I\/R injury was used to evaluate the effects of 7-day prophylactic CYPs treatment (400 mg\/kg). Echocardiographic and histological analyses were performed, and serum myocardial injury biomarkers, oxidative stress indicators, pro-inflammatory cytokines, mitochondrial ultrastructure, ATP bioenergetics, mitochondrial respiratory chain gene expression, and gut microbiota composition were assessed. Results: Echocardiographic and histological analyses revealed that CYPs pretreatment significantly ameliorated cardiac dysfunction, as indicated by increased LVEF from 28.98% to 57.68% and reduced myocardial infarct size by 36.73% compared with the I\/R group and decreased serum myocardial injury biomarkers, including CK-MB, LDH, and LDH-1. Mechanistically, CYPs exerted robust cardioprotection by mitigating oxidative damage, with MDA levels reduced by 28.83% and SOD activity increased to 1.76-fold that of the I\/R group, and suppressing the release of pro-inflammatory cytokines, including Tnf-\u03b1, Il-6, and Il-1\u03b2. Crucially, CYPs intervention preserved mitochondrial ultrastructure and ATP bioenergetics, and levels increased to 1.51-fold that of the I\/R group and upregulated the expression of essential mitochondrial respiratory chain genes, including mt-Nd1, mt-Nd4l, mt-Cyb, mt-CoII, and mt-Atp6. Furthermore, 16S rRNA sequencing showed that CYPs treatment reshaped gut microbiota and elevated the relative abundance of anti-inflammatory and antioxidant beneficial genus Akkermansia. Conclusions: Collectively, these findings provide novel evidence that CYPs confer profound protection against myocardial I\/R injury through a multitargeted network involving the restoration of mitochondrial homeostasis, attenuation of oxidative inflammation, and modulation of the gut microbiome, highlighting CYPs as a promising functional food-derived candidate for adjunctive therapy in ischemic heart disease.<\/jats:p>","DOI":"10.3390\/nu18152464","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T08:52:01Z","timestamp":1785228721000},"page":"2464","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Chinese Yam Polysaccharides Alleviate Myocardial Ischemia\/Reperfusion Injury by Modulating Gut Microbiota, Restoring Mitochondrial Function, and Reducing Oxidative Stress"],"prefix":"10.3390","volume":"18","author":[{"given":"Zhengyang","family":"Zhang","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":"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":"Zhixi","family":"Wei","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":[[2026,7,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1161\/CIRCRESAHA.124.326029","article-title":"GUCY1A1-LDHA axis suppresses ferroptosis in cardiac ischemia-reperfusion injury","volume":"137","author":"Yin","year":"2025","journal-title":"Circ. 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