Epigenetic remodeling drives autophagy dysfunction in cardiometabolic HFpEF

Background Cardiometabolic heart failure with preserved ejection fraction (cHFpEF) is a prevalent condition with incompletely defined molecular mechanisms. Impaired autophagy has emerged as a contributor to disease progression, and epigenetic regulators may link environmental stressors to maladaptive gene expression. Bromodomain and extraterminal domain (BET) proteins act as epigenetic readers of acetylated histones and represent promising therapeutic targets; however, their role in cardiac autophagy regulation remains unclear. We hypothesized that BET proteins contribute to autophagy dysregulation in cHFpEF and that pharmacological BET inhibition restores autophagic flux and cardiac function. Methods A mouse model of cHFpEF induced by combined metabolic and hemodynamic stress for 15 weeks was studied. Single-nuclei RNA sequencing (snRNAseq, 10x Genomics platform) characterised cell type-specific transcriptional alterations with emphasis on autophagy pathways. Intercellular communication was inferred using CellChat, and transcription factor activity analysis identified regulatory drivers. Chromatin immunoprecipitation sequencing (ChIPseq) assessed histone modification patterns at autophagy-associated loci. Pathway enrichment was performed using Reactome gene sets and GSEA with FDR correction. cHFpEF and Control mice were treated for 21 days with Vehicle or the selective BET inhibitor RVX-208 (Apabetalone). Cardiac function was evaluated by echocardiography, autophagy-related gene expression was quantified using a custom PCR array, and palmitic acid treated cardiomyocytes were used as an in vitro metabolic stress model. Results snRNAseq demonstrated significant downregulation of autophagy-related genes in cHFpEF hearts. A distinct cardiomyocyte subpopulation exhibited impaired autophagic signatures, activation of mTOR and calcineurin signaling, oxidative stress, altered mitochondrial dynamics, and increased apoptotic pathways. CellChat analysis placed these cardiomyocytes at the center of a rewired intercellular network with intensified crosstalk to immune cells, particularly macrophages, linking autophagy dysfunction to inflammatory remodeling. Epigenomic profiling revealed enrichment of active chromatin marks (H3K27ac) at autophagy- and stress-responsive loci, consistent with BET-dependent regulation. BET inhibition with RVX-208 restored autophagy-related transcriptional programs and significantly improved diastolic function and exercise capacity. Conclusions BET-mediated epigenetic remodeling in cardiomyocytes represents a central mechanism driving autophagy impairment in cHFpEF. Pharmacological BET inhibition restores autophagic signaling and improves cardiac function, highlighting BET proteins as potential therapeutic targets.