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Histone deacetylase 6 (HDAC6) participates in the progression of multiple cardiovascular diseases, including chronic hypertension, ischemic stroke, and acute cardiac injury. A delicate balance of autophagy regulates heart homeostasis, whereas dysregulated autophagy is involved in myocardial hypertrophy. However, whether HDAC6 participates in pathological cardiac hypertrophy by regulating autophagy remains unclear. In this paper, we report for the first time that HDAC6 is involved in isoproterenol (ISO)\u2010induced pathological cardiac hypertrophy by interacting with and ubiquitinating MAP1LC3B. First, the expression level of HDAC6 was found to be increased in cardiac hypertrophy models induced by ISO. <jats:italic>HDAC6<\/jats:italic> overexpression promoted the expression of hypertrophic genes and enhanced cell surface area. Conversely, HDAC6 inhibition attenuated ISO\u2010induced hypertrophic responses. Mechanistically, HDAC6 promoted hypertrophic responses by negatively regulating autophagy. Furthermore, HDAC6 interacted with MAP1LC3B and mediated its monoubiquitination, thereby contributing to reduced MAP1LC3B levels and impaired autophagy. Inhibition of HDAC6 activity in mice abrogated the hypertrophic effects of ISO by restoring MAP1LC3B expression. In summary, our data demonstrate that HDAC6 participates in ISO\u2010induced cardiac hypertrophy by limiting the availability of MAP1LC3B and suppressing autophagy. \u00a9 2025 The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.6419","type":"journal-article","created":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T05:22:47Z","timestamp":1744348967000},"page":"217-229","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Histone deacetylase 6 inhibition attenuates pathological cardiac hypertrophy by promoting autophagy through <scp>MAP1LC3B<\/scp> ubiquitination"],"prefix":"10.1002","volume":"266","author":[{"given":"Jiayu","family":"Yao","sequence":"first","affiliation":[{"name":"School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease Southeast University  Nanjing PR 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