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Phyllanthus amarus exhibits anti-inflammatory, antiviral, anticancer, antioxidant, nephroprotective, and hepatoprotective effects. However, its potential against DOX-induced acute cardiotoxicity is lacking. This study aimed to assess the underlying mechanism of action of P. amarus against DOX-induced acute cardiotoxicity in Sprague\u2013Dawley rats. Phyllanthin was isolated from the methanolic extract of the aerial parts of P. amarus and characterized using HPLC-ESI-MS\/MS. Its cardioprotective efficacy was evaluated in DOX-intoxicated male Sprague\u2013Dawley rats (200\u2013230\u00a0g) at doses of 50, 100, and 200\u00a0mg\/kg, p.o., by examining electrocardiographic, hemodynamic, histological, and biochemical parameters. In the results, spectral analysis revealed that the isolated phyllanthin has a molecular formula of C24H34O6 and a molecular weight of 418.1534\u00a0Da. P. amarus (50 and 100\u00a0mg\/kg) effectively (P\u00a0&amp;lt;\u20090.05) alleviated DOX-induced cardiac injury by ameliorating deviations in heart weight, electrocardiographic and hemodynamic function, and serum biomarkers (CK-MB, LDH, AST, ALP, and ALT). Moreover, it notably (P\u00a0&amp;lt;\u20090.05) reduced cardiac oxidative stress and cTn-I, ANP, BNP, ILs, TNF-\u03b1, and nitric oxide levels. Additionally, P. amarus effectively (P\u00a0&amp;lt;\u20090.05) up-regulated Bcl2 and down-regulated (P\u00a0&amp;lt;\u20090.05) caspase-3 and Bax protein levels. Furthermore, it effectively (P&amp;lt;0.05) ameliorated the DOX-induced histological abnormalities in cardiac tissue. In conclusion, this study suggests that Phyllanthin from P. amarus exerts cardioprotective effects by modulating the Bax\/Bcl2 and caspase-3 pathways to suppress the expression of pro-inflammatory cytokines, apoptosis, and cardio-oxido-nitrosative stress. Thus, Phyllanthin can be considered as a potential therapy for the treatment of DOX-induced acute cardiotoxicity.<\/jats:p>","DOI":"10.1093\/toxres\/tfaf160","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T13:09:25Z","timestamp":1762434565000},"source":"Crossref","is-referenced-by-count":0,"title":["Phyllanthin mitigates doxorubicin-induced acute cardiotoxicity: role of Bax\/Bcl2 and Caspase-3 regulation"],"prefix":"10.1093","volume":"14","author":[{"given":"Xumei","family":"He","sequence":"first","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital of Xi\u2019an Jiaotong University , 277 West Yanta Road, Xi\u2019an, Shaanxi 710061 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowei","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, First Affiliated Hospital of Xi\u2019an Jiaotong University , 277 West Yanta Road, Xi\u2019an, Shaanxi 710061 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Rizhao People\u2019s Hospital , No. 126, Tai\u2019an Road, Donggang District, RiZhao 276825 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3425-7549","authenticated-orcid":false,"given":"Xiuyuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Rizhao People\u2019s Hospital , No. 126, Tai\u2019an Road, Donggang District, RiZhao 276825 ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,11,23]]},"reference":[{"key":"2025112306121805100_ref1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1517\/17425255.2012.645536","article-title":"The contribution of oxidative stress to drug-induced organ toxicity and its detection in vitro and in vivo","volume":"8","author":"Pereira","year":"2012","journal-title":"Expert Opin Drug Metab Toxicol"},{"key":"2025112306121805100_ref2","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.ejphar.2017.10.043","article-title":"Molecular mechanism of doxorubicin-induced cardiomyopathy\u2013An update","volume":"818","author":"Renu","year":"2018","journal-title":"Eur J Pharmacol"},{"key":"2025112306121805100_ref3","doi-asserted-by":"publisher","first-page":"111708","DOI":"10.1016\/j.biopha.2021.111708","article-title":"Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management","volume":"139","author":"Rawat","year":"2021","journal-title":"Biomed Pharmacother"},{"key":"2025112306121805100_ref4","doi-asserted-by":"publisher","first-page":"1262","DOI":"10.3389\/fphar.2018.01262","article-title":"Updates in anthracycline-mediated cardiotoxicity","volume":"9","author":"Nebigil","year":"2018","journal-title":"Front Pharmacol"},{"key":"2025112306121805100_ref5","doi-asserted-by":"publisher","first-page":"8863789","DOI":"10.1155\/2021\/8863789","article-title":"Role of oxidative stress in the mechanisms of anthracycline-induced cardiotoxicity: effects of preventive strategies","volume":"2021","author":"Carrasco","year":"2021","journal-title":"Oxidative Med Cell Longev"},{"key":"2025112306121805100_ref6","doi-asserted-by":"publisher","first-page":"1946","DOI":"10.3390\/molecules26071946","article-title":"Protective effect of two alkaloids from Hippophae rhamnoides Linn. 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