{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:42:43Z","timestamp":1785213763103,"version":"3.55.0"},"reference-count":48,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"15","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,8,5]]},"abstract":"<jats:sec xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Doxorubicin is an effective chemotherapy drug used to treat various types of cancer. However, doxorubicin treatment is associated with cardiotoxicity, which limits its clinical use. Exercise can benefit both cancer and cardiovascular disease. Clustered regularly interspaced short palindromic repeat (CRISPR)\u2010Cas13 (CRISPR\u2010associated protein 13) platforms have emerged as effective technologies for targeting the expression of RNA in transcript levels. To develop exercise mimetics that can mimic the beneficial effects of exercise training to attenuate doxorubicin\u2010induced cardiotoxicity, we are using the CRISPR\u2010\n              <jats:italic toggle=\"no\">hf<\/jats:italic>\n              (\n              <jats:italic toggle=\"no\">high\u2010fidelity<\/jats:italic>\n              )Cas13x system.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Adult male mice were swim\u2010trained twice a day for 4\u2009weeks to induce exercise\u2010induced physiological cardiac hypertrophy. Adeno\u2010associated virus 9\u2010mediated METTL14 (methyltransferase\u2010like 14) overexpression under the cardiac\u2010specific\n              <jats:italic toggle=\"no\">ctnt<\/jats:italic>\n              promoter was used to overexpression METTL14 in\u00a0vivo. RNA N\n              <jats:sup>6<\/jats:sup>\n              \u2010methyladenosine inhibitor STM2457 was used to modulate global total RNA m\n              <jats:sup>6<\/jats:sup>\n              A levels in\u00a0vivo. CRISPR\u2010cr3\u20104\/\n              <jats:italic toggle=\"no\">hf<\/jats:italic>\n              Cas13x system was generated by\n              <jats:italic toggle=\"no\">hf<\/jats:italic>\n              Cas13x guided crRNA3 and crRNA4 targeting the\n              <jats:italic toggle=\"no\">Mettl14<\/jats:italic>\n              expressed under\n              <jats:italic toggle=\"no\">ctnt<\/jats:italic>\n              promoter and packaged in an adeno\u2010associated virus 9.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Swimming exercise alleviated doxorubicin\u2010induced cardiotoxicity. METTL14 was increased in doxorubicin\u2010treated hearts but decreased in exercised hearts. METTL14 overexpression inhibited exercise\u2010induced physiological cardiac hypertrophy. Conversely, STM2457 treatment reversed the suppressive effects of METTL14 overexpression on the physiological cardiac hypertrophy induced by exercise. Treatment with CRISPR\u2010cr3\u20104\/\n              <jats:italic toggle=\"no\">hf<\/jats:italic>\n              Cas13x effectively inhibiting the expression of METTL14 in the heart, alleviating doxorubicin treatment\u2010induced cardiac dysfunction and cardiac fibrosis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Our results suggest that the CRISPR\u2010\n              <jats:italic toggle=\"no\">hf<\/jats:italic>\n              Cas13x system has the potential for generating exercise mimetics. Mimicking exercise by RNA\u2010targeting\n              <jats:italic toggle=\"no\">Mettl14<\/jats:italic>\n              suppression could be a therapeutic strategy for doxorubicin\u2010induced cardiotoxicity.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.124.040700","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T12:06:14Z","timestamp":1752753974000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting\n            <i>Mettl14<\/i>\n            Using an RNA\u2010Targeting Clustered Regularly Interspaced Short Palindromic Repeat\u2010\n            <i>High\u2010Fidelity<\/i>\n            Cas13x System Attenuates Doxorubicin\u2010Induced Cardiotoxicity"],"prefix":"10.1161","volume":"14","author":[{"given":"Wensi","family":"Wan","sequence":"first","affiliation":[{"name":"Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People\u2019s Hospital of Nantong) and School of Life Sciences, Shanghai University","place":["Nantong, China"]},{"name":"Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education), School of Life Sciences, Shanghai University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caiyue","family":"Cui","sequence":"additional","affiliation":[{"name":"Cardiac Regeneration and Ageing Lab, Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People\u2019s Hospital of Nantong) and School of Life Sciences, Shanghai University","place":["Nantong, China"]},{"name":"Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, Joint International Research Laboratory 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