{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T00:32:43Z","timestamp":1789173163138,"version":"build-2803163510"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"16","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,8,19]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Doxorubicin, a broad\u2010spectrum chemotherapy drug, is often associated with dosage\u2010dependent cardiotoxicity, which results in its limited clinical application. A therapeutic dose of doxorubicin can activate cardiac ubiquitin\u2010proteasome system, whereas the role and potential mechanisms of this process in doxorubicin\u2010induced cardiomyopathy (DIC) remain unclear. Herein, we assessed the potential role and therapeutic value of RNF2 (ring finger protein 2) on doxorubicin\u2010induced cardiac damage.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods<\/jats:title>\n            <jats:p xml:lang=\"en\">Cardiomyocyte\u2010specific RNF2 knockout or overexpression mice received doxorubicin intraperitoneal injection to establish the DIC model. The effects of RNF2 and its downstream mediators were explored through RNA sequencing, immunoprecipitation mass spectrometry analysis, and protein pulldown analysis.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              The expression of RNF2 was significantly increased in doxorubicin\u2010treated murine myocardium and neonatal rat ventricular myocytes. Cardiomyocyte\u2010specific RNF2 overexpression resulted in exaggerated DIC accompanied by increased cardiac dysfunction, fibrosis and apoptosis. Cardiac damage was mitigated in \u03b1\u2010myosin heavy chain promoter\u2010driven heterozygous\u2010Cre\n              <jats:sup>+<\/jats:sup>\n              \/RNF2\u2010floxed mice. Previous studies have demonstrated that mitochondrial dysfunction and oxidative stress are crucial in DIC and are promoted by RNF2 overexpression and impeded by RNF2 knockout. Mechanistically, RNF2 directly interacted with mercaptopyruvate sulfurtransferase, followed by the ubiquitination and accelerated degradation of mercaptopyruvate sulfurtransferase to decrease hydrogen sulfide accumulation, thereby contributing to more severe oxidative damage and mitochondrial morphofunctional defects. Moreover, mercaptopyruvate sulfurtransferase overexpression or hydrogen sulfide supplementation in cardiomyocyte\u2010specific RNF2\u2010overexpressing mice restored cardiac performance after doxorubicin challenge.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">Our findings reveal the role of RNF2 in oxidative stress and mitochondrial homeostasis and the progression of DIC, suggesting that targeting RNF2 may be a potential therapeutic benefit for DIC.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.125.041440","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T10:52:14Z","timestamp":1754477534000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Ring Finger Protein 2 Promotes Oxidative Stress and Mitochondrial Dysfunction in Doxorubicin\u2010Induced Cardiotoxicity Via the Mercaptopyruvate Sulfurtransferase\/Hydrogen Sulfide Pathway"],"prefix":"10.1161","volume":"14","author":[{"given":"Yi","family":"Zhong","sequence":"first","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Fan","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxiang","family":"Mao","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoqing","family":"Liu","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7185-2671","authenticated-orcid":false,"given":"Cheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7884-0745","authenticated-orcid":false,"given":"Qiubai","family":"Li","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology","place":["Wuhan, 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