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Figure 2. Sex-specific epigenetic regulation of cardiac gene expression. Males exhibit reduced activity of Y-linked histone demethylases (UTY, KDM5D) and greater HDAC-mediated repression of MEF2-PGC1α signaling, contributing to mitochondrial dysfunction and maladaptive remodeling. Androgen signaling may further influence DNMT activity and DNA methylation patterns. Females express higher levels of X-linked demethylases (KDM5C, KDM6A) that escape X-inactivation and benefit from estrogen-mediated recruitment of coactivators such as CBP/p300, enhancing histone acetylation and demethylation. These combined mechanisms underlie differences in cardiac remodeling, heart failure progression, and myocardial infarction risk between men and women. UTY: ubiquitously transcribed tetratricopeptide repeat containing: Y-linked; KDM5D: lysine demethylase 5D; HDAC: histone deacetylase; MEF2: myocyte enhancer factor 2; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator-1 alpha; DNMT: DNA methyltransferase; KDM5C: lysine demethylase 5C; KDM6A (UTX): lysine demethylase 6A; CBP: CREB-binding protein; p300: E1A-binding protein p300. Created in BioRender. Stephens, S. (2026) https://BioRender.com/n26cejf.