{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T01:51:37Z","timestamp":1792547497781,"version":"4.5.0"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","funder":[{"DOI":"10.13039\/501100012165","name":"MOST | Key Technologies Research and Development Program","doi-asserted-by":"publisher","award":["2016YFA0100900"],"award-info":[{"award-number":["2016YFA0100900"]}],"id":[{"id":"10.13039\/501100012165","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81530058"],"award-info":[{"award-number":["81530058"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010896","name":"NSF | International Cooperation and Exchange Programme","doi-asserted-by":"publisher","award":["81820108019"],"award-info":[{"award-number":["81820108019"]}],"id":[{"id":"10.13039\/501100010896","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81571841"],"award-info":[{"award-number":["81571841"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81974035"],"award-info":[{"award-number":["81974035"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81871516"],"award-info":[{"award-number":["81871516"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201703170139"],"award-info":[{"award-number":["201703170139"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2020,7,31]]},"abstract":"<jats:sec>\n                    <jats:title>Rationale:<\/jats:title>\n                    <jats:p>Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is restricted because it poses a risk of severe cardiotoxicity. Previous work has established that CircITCH (circular RNA ITCH [E3 ubiquitin-protein ligase]) is a broad-spectrum tumor-suppressive circular RNA and that its host gene, ITCH (E3 ubiquitin protein ligase), is involved in doxorubicin-induced cardiotoxicity (DOXIC). Whether CircITCH plays a role in DOXIC remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective:<\/jats:title>\n                    <jats:p>We aimed to dissect the role of CircITCH in DOXIC and further decipher its potential mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results:<\/jats:title>\n                    <jats:p>\n                      Circular RNA sequencing was performed to screen the potentially involved circRNAs in DOXI pathogenesis. Quantitative polymerase chain reaction and RNA in situ hybridization revealed that CircITCH was downregulated in doxorubicin-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in the autopsy specimens from cancer patients who suffered from doxorubicin-induced cardiomyopathy. Cell death\/viability assays, detection of cardiomyocyte necrosis markers, microelectrode array, and cardiomyocyte functional assays revealed that CircITCH ameliorated doxorubicin-induced cardiomyocyte injury and dysfunction. Detection of cellular\/mitochondrial oxidative stress and DNA damage markers verified that CircITCH alleviated cellular\/mitochondrial oxidative stress and DNA damage induced by doxorubicin. RNA pull-down assays, Ago2 immunoprecipitation and double fluorescent in situ hybridization identified miR-330-5p as a direct target of CircITCH. Moreover, CircITCH was found to function by acting as an endogenous sponge that sequestered miR-330-5p. Bioinformatic analysis, luciferase reporter assays, and quantitative polymerase chain reaction showed that SIRT6 (sirtuin 6), BIRC5 (baculoviral IAP repeat containing 5, Survivin), and ATP2A2 (ATPase sarcoplasmic\/endoplasmic reticulum Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transporting 2, SERCA2a [SR Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -ATPase 2]) were direct targets of miR-330-5p and that they were regulated by the CircITCH\/miR-330-5p axis in DOXIC. Further experiments demonstrated that CircITCH-mediated alleviation of DOXIC was dependent on the interactions between miR-330-5p and the 3\u2032-UTRs of SIRT6, BIRC5, and ATP2A2 mRNA. Finally, AAV9 (adeno-associated virus serotype 9) vector-based overexpression of the well-conserved CircITCH partly prevented DOXIC in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>CircITCH represents a novel therapeutic target for DOXIC because it acts as a natural sponge of miR-330-5p, thereby upregulating SIRT6, Survivin and SERCA2a to alleviate doxorubicin-induced cardiomyocyte injury and dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.119.316061","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T12:13:23Z","timestamp":1589199203000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":167,"title":["The Tumor-Suppressive Human Circular RNA CircITCH Sponges miR-330-5p to Ameliorate Doxorubicin-Induced Cardiotoxicity Through Upregulating SIRT6, Survivin, and SERCA2a"],"prefix":"10.1161","volume":"127","author":[{"given":"Dong","family":"Han","sequence":"first","affiliation":[{"name":"From the Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing (D.H., J.Z., Yabin Wang, F.C.)"},{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019an Shaanxi Province, China (D.H., X.D., J.C., F.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei Province, China (Yongjun Wang, T.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yabin","family":"Wang","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing (D.H., J.Z., Yabin Wang, F.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchun","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019an Shaanxi Province, China (D.H., X.D., J.C., F.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingwen","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan Hubei Province, China (Yongjun Wang, T.Z.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangwei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019an Shaanxi Province, China (D.H., X.D., J.C., F.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jibin","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing (D.H., J.Z., Yabin Wang, F.C.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1010-6429","authenticated-orcid":true,"given":"Feng","family":"Cao","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, National Clinical Research Center for Geriatric Diseases, 2nd Medical Center, Chinese PLA General Hospital, Beijing (D.H., J.Z., Yabin Wang, F.C.)"},{"name":"Department of Cardiology, Xijing Hospital, Air Force Medical University, Xi\u2019an Shaanxi Province, China (D.H., X.D., J.C., 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