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Osteocrin (OSTN) is a novel secretory peptide mainly derived from the bone and skeletal muscle, and plays critical roles in regulating bone growth and physical endurance. Inspiringly, OSTN was also reported to be abundant in the myocardium that functioned as a therapeutic agent against cardiac rupture and congestive heart failure in mice after myocardial infarction. Herein, we investigated the role and potential mechanism of OSTN in DOX\u2010induced cardiotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cardiac\u2010restrict OSTN overexpression was performed by the intravenous injection of a cardiotropic AAV9 vector, and subsequently the mice received 15\u00a0mg\/kg DOX injection (i.p., once) to induce acute cardiac injury. Besides, H9C2 cell lines were used to assess the possible role of OSTN in vitro by incubating with recombinant human OSTN or small interfering RNA against <jats:italic>Ostn<\/jats:italic> (si<jats:italic>Ostn<\/jats:italic>). To clarify the involvement of protein kinase G (PKG), KT5823 and si<jats:italic>Pkg<\/jats:italic> were used in vivo and in vitro. Mice were also administrated intraperitoneally with 5\u00a0mg\/kg DOX weekly for consecutive 3\u00a0weeks at a cumulative dose of 15\u00a0mg\/kg to mimic the cardiotoxic effects upon chronic DOX exposure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>OSTN treatment notably attenuated, whereas OSTN silence exacerbated inflammation, oxidative stress, and cardiomyocyte apoptosis in DOX\u2010treated H9C2 cells. Besides, cardiac\u2010restrict OSTN\u2010overexpressed mice showed an alleviated cardiac injury and malfunction upon DOX injection. Mechanistically, we found that OSTN activated PKG, while PKG inhibition abrogated the beneficial effect of OSTN in vivo and in vitro. As expected, OSTN overexpression also improved cardiac function and survival rate in mice after chronic DOX treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>OSTN protects against DOX\u2010elicited inflammation, oxidative stress, apoptosis, and cardiac dysfunction via activating PKG, and cardiac gene therapy with OSTN provides a novel therapeutic strategy against DOX\u2010induced cardiotoxicity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.124","type":"journal-article","created":{"date-parts":[[2020,7,3]],"date-time":"2020-07-03T10:40:44Z","timestamp":1593772844000},"source":"Crossref","is-referenced-by-count":167,"title":["Osteocrin attenuates inflammation, oxidative stress, apoptosis, and cardiac dysfunction in doxorubicin\u2010induced cardiotoxicity"],"prefix":"10.1002","volume":"10","author":[{"given":"Can","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan P. R. 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