{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T06:35:31Z","timestamp":1776926131417,"version":"3.51.2"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Doxorubicin (DOX) is a highly effective chemotherapeutic agent, but its severe cardiotoxicity limits its clinical use. This study aimed to investigate whether the natural compound Arctiin can alleviate DOX-induced cardiomyopathy and its underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>DOX-treated H9C2 cardiomyocytes and mouse models were used. Cardiac function, myocardial injury, oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and lipid metabolism were assessed by echocardiography, histological staining, molecular biology assays, and lipidomics. SIRT1 knockdown\/knockout models were employed to verify its necessity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Arctiin significantly improved DOX-induced cardiac dysfunction and myocardial damage in mice. Mechanistically, Arctiin directly binds to the SIRT1 protein and disrupts its interaction with the E3 ubiquitin ligase SMURF2, thereby suppressing SIRT1 ubiquitination and subsequent proteasomal degradation, ultimately stabilizing and upregulating SIRT1 protein levels. The activated SIRT1 then upregulates the expression of its downstream effectors, NRF2 and HO-1, collectively alleviating oxidative stress and ER stress and inhibiting apoptosis in cardiomyocytes. Furthermore, lipidomics analysis revealed that Arctiin reversed DOX-induced cardiac lipid metabolic dysregulation in a SIRT1-dependent manner. However, all these protective effects of Arctiin were completely abolished in SIRT1-knockdown or knockout cell and mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates that Arctiin targets the SIRT1 protein and inhibits its SMURF2-mediated ubiquitination and degradation, thereby stabilizing and activating the SIRT1\/NRF2 pathway. This leads to improved lipid metabolism, reduced oxidative and ER stress, and ultimately protection against DOX-induced cardiotoxicity. These findings provide a novel theoretical basis for Arctiin as a potential cardioprotective agent.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1797815","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T05:36:19Z","timestamp":1776922579000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting SIRT1 stability: arctiin ameliorates doxorubicin-induced cardiac injury by inhibiting SMURF2 binding and enhancing protective lipid metabolism"],"prefix":"10.3389","volume":"17","author":[{"given":"Teng","family":"Teng","sequence":"first","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yujia","family":"Huo","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhuoyu","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiyang","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yupei","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sichi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qizhu","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Renmin Hospital of Wuhan University","place":["Wuhan, China"]},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases","place":["Wuhan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.febslet.2012.11.019","article-title":"Doxorubicin treatment inhibits PPARgamma and may induce lipotoxicity by mimicking a type 2 diabetes-like condition in rodent models","volume":"587","author":"Arunachalam","year":"2013","journal-title":"FEBS Lett."},{"key":"B2","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/0717-6287-47-50","article-title":"Arctiin blocks hydrogen peroxide-induced senescence and cell death though microRNA expression changes in human dermal papilla cells","volume":"47","author":"Bae","year":"2014","journal-title":"Biol. 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