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Its role in cardiac hypertrophy remains to be elucidated. We investigated its effects on cardiac hypertrophy along with the potential mechanisms involved.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The effects of limonin on cardiac hypertrophy in C57\/BL6 mice caused by aortic banding, plus neonatal rat cardiac myocytes (NRCMs) stimulated with phenylephrine to induce cardiomyocyte hypertrophy <jats:italic>in vitro<\/jats:italic> were investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Limonin markedly improved the cardiac function and heart weight in aortic banded mice. Limonin\u2010treated mice and NRCMs also produced fewer cardiac hypertrophy markers than those treated with the vehicle in the hypertrophic groups. Sustained aortic banding\u2010 or phenylephrine\u2010stimulation impaired cardiac sirtuin 6 (SIRT6) protein levels, which were partially reversed by limonin associated with enhanced activity of PPAR\u03b1. <jats:italic>Sirt6<\/jats:italic> siRNA inhibited the anti\u2010hypertrophic effects of limonin <jats:italic>in vitro<\/jats:italic>. Interestingly, limonin did not influence <jats:italic>Sirt6<\/jats:italic> mRNA levels, but regulated ubiquitin levels. Thus, the protein biosynthesis inhibitor, cycloheximide and proteasome inhibitor, MG\u2010132, were used to determine SIRT6 protein expression levels. Under phenylephrine stimulation, limonin increased SIRT6 protein levels in the presence of cycloheximide, but it did not influence SIRT6 expression in the presence of MG\u2010132, suggesting that limonin promotes SIRT6 levels by inhibiting its ubiquitination degradation. Furthermore, limonin inhibited the degradation of SIRT6 by activating ubiquitin\u2010specific peptidase 10 (USP10), while <jats:italic>Usp10<\/jats:italic> siRNA prevented the beneficial effects of limonin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Limonin mediates the ubiquitination and degradation of SIRT6 by activating USP10, providing an attractive therapeutic target for cardiac hypertrophy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15899","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T15:26:52Z","timestamp":1655825212000},"page":"4516-4533","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Limonin stabilises sirtuin 6 (SIRT6) by activating ubiquitin specific peptidase 10 (USP10) in cardiac hypertrophy"],"prefix":"10.1111","volume":"179","author":[{"given":"Li\u2010Bo","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Si\u2010Hui","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Liang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Cardiology Renmin Hospital of Wuhan University  Wuhan China"},{"name":"Hubei Key Laboratory of Metabolic and Chronic Diseases  Wuhan 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