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Despite their therapeutic promise, clinical studies have reported cardiac side effects, particularly electrocardiogram (EKG) abnormalities, with QT interval prolongation being one of the most consistently reported findings. The mechanisms underlying these cardiac effects remain unclear. In this study, we investigated the role of HDAC3 in cardiac electrophysiology. We found that postnatal depletion of cardiac HDAC3 in mice caused QT interval prolongation, recapitulating the EKG abnormalities reported with HDAC inhibitor use. Adult-onset inducible depletion of cardiac HDAC3 induced additional EKG abnormalities, including T-wave flattening, inversion, and biphasic T waves, which are also observed clinically. Loss of HDAC3 deacetylase activity, without affecting HDAC3 protein levels, was sufficient to induce QT prolongation. Disruption of HDAC3 function altered the expression of ion channel genes, including the downregulation of potassium channel genes such as Kcnh2, Kcne1, and Kcnip2. Moreover, a single dose of HDAC inhibitors, romidepsin or mocetinostat, caused reversible QT prolongation in mice. Consistent with these findings, HDAC inhibitor treatment altered the expression of potassium channel genes, with a predominant downregulation of multiple Kcn family members, including Kcnq1, Kcnh2, and Kcnip2. These findings establish HDAC3 enzymatic activity as a key regulator of cardiac repolarization and provide mechanistic insight into HDAC inhibitor-associated cardiotoxicity.<\/jats:p>","DOI":"10.3390\/cells15100902","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"902","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiac HDAC3 Disruption Contributes to HDAC Inhibitor-Induced QT Prolongation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-417X","authenticated-orcid":false,"given":"Jiao","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, One Baylor Plaza, R616 ABBR Bldg., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3445-6327","authenticated-orcid":false,"given":"Christopher","family":"Ward","sequence":"additional","affiliation":[{"name":"Department of Integrative Physiology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sichong","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, One Baylor Plaza, R616 ABBR Bldg., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3707-7557","authenticated-orcid":false,"given":"Jiang","family":"Chang","sequence":"additional","affiliation":[{"name":"Institute for Biosciences and Technology, Center for Genomics and Precision Medicine, Texas A&M University, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6858-0633","authenticated-orcid":false,"given":"Zheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, One Baylor Plaza, R616 ABBR Bldg., Houston, TX 77030, USA"},{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, R616 ABBR Bldg., Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nrm2346","article-title":"The Rpd3\/Hda1 family of lysine deacetylases: From bacteria and yeast to mice and men","volume":"9","author":"Yang","year":"2008","journal-title":"Nat. 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