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Celastrol (Cel), a bioactive triterpenoid from Tripterygium wilfordii, has recognized anti-inflammatory and antioxidant activities, but its potential for treating DOX-induced heart failure remains unclear. This study investigated the cardioprotective effects of Cel in a murine model of DOX-induced heart failure. Methods: Cardiac function was assessed by echocardiography, while serum biochemical assays, histological staining, transmission electron microscopy, RT-qPCR, ATP measurement, and 16S rRNA sequencing were used to evaluate myocardial injury, oxidative stress, mitochondrial structure and function, fibrosis, and gut microbial composition. Results: Cel improved survival, left ventricular ejection fraction, fractional shortening, and cardiac output, while reducing LDH, LDH-1, CK, CK-MB, AST, Anp, and Bnp. It also decreased malondialdehyde levels, increased superoxide dismutase and glutathione peroxidase activities, alleviated mitochondrial swelling and cristae disruption, restored ATP production, and reduced myocardial fibrosis. In addition, Cel was associated with improved gut microbial diversity and composition, with Bacteroides and Allobaculum showing associations with host metabolic, antioxidant, and inflammatory indices. Conclusions: Cel attenuated DOX-induced cardiac injury by preserving mitochondrial integrity, improving redox and energy homeostasis, and limiting pathological remodeling. These cardioprotective effects were also accompanied by alterations in gut microbial composition, suggesting that Cel may represent a promising strategy for mitigating DOX-induced cardiotoxicity.<\/jats:p>","DOI":"10.3390\/ph19091494","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1494","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Celastrol Attenuates Doxorubicin-Induced Heart Failure by Preserving Mitochondrial Integrity and Suppressing Oxidative Stress and Is Accompanied by Changes in Gut Microbiota"],"prefix":"10.3390","volume":"19","author":[{"given":"Yang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Jingyi","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Mingyang","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Yufang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Xinyu","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Chang","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Sitong","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Peng","family":"An","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"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"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"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"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6095","DOI":"10.1111\/febs.15583","article-title":"New insights into the activities and toxicities of the old anticancer drug doxorubicin","volume":"288","author":"Qiao","year":"2021","journal-title":"FEBS J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.1007\/s00204-025-04112-1","article-title":"A recent decade update on combating doxorubicin-induced toxicities","volume":"99","author":"Sritharan","year":"2025","journal-title":"Arch. 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