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Maladaptive transcriptional programs drive the fibrosis, hypertrophy, and vascular inflammation that characterize these pathologies. Histone posttranslational modifications regulate these programs by remodeling chromatin accessibility and transcriptional output in cardiomyocytes, vascular cells, and immune cells. These modifications include methylation, acetylation, and metabolite\u2010derived acylations. While the enzymatic machinery of classical histone marks is increasingly well defined, the cell\u2010type\u2010specific integration of these regulators into dynamic cardiovascular networks remains incompletely understood. This narrative review summarizes experimental and human studies published up to early 2026. We examine how classical marks such as H3K27me3 and H3K9ac, alongside emerging metabolic sensors like histone lysine lactylation, shape core pathobiological programs, including oxidative stress responses, endothelial dysfunction, and extracellular matrix remodeling, across major cardiovascular syndromes. We further critically evaluate the enzymatic machinery and pharmacological strategies by contrasting broad\u2010spectrum histone deacetylase inhibition with precision approaches, including bromodomain inhibition and locus\u2010selective epigenome editing. Finally, we address translational constraints such as drug delivery and off\u2010target effects. We propose that single\u2010cell resolution and spatial multiomics will be essential to identify compartment\u2010specific targets and advance precision cardiovascular epigenetic therapeutics.<\/jats:p>","DOI":"10.1002\/mco2.70765","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T07:29:03Z","timestamp":1778657343000},"source":"Crossref","is-referenced-by-count":5,"title":["Histone Modifications in Cardiovascular Disease: Mechanisms and Therapeutic Opportunities"],"prefix":"10.1002","volume":"7","author":[{"given":"Yu","family":"Zheng","sequence":"first","affiliation":[{"name":"School of Chinese Medicine Hunan University of Chinese Medicine  Changsha China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Xuan","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine Hunan University of Chinese Medicine  Changsha 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