Epigenetic activation of HMGCS2 by SETD7 drives metabolic remodeling and diastolic dysfunction in obese HFpEF

Background Obese heart failure with preserved ejection fraction (obHFpEF) is projected to markedly increase in prevalence and is associated with substantial morbidity and mortality. Despite its growing burden, the molecular mechanisms driving disease progression remain incompletely understood. Emerging evidence highlights epigenetic remodeling as a central determinant of cardiometabolic dysfunction in HFpEF. In particular, histone lysine methylation critically regulates transcriptional programs governing myocardial metabolism. Purpose To investigate whether the histone methyltransferase SETD7 promotes obHFpEF through epigenetic activation. Methods Unbiased profiling of chromatin-modifying enzymes was performed in left ventricular (LV) myocardial specimens from obHFpEF patients and age-matched controls (n=10/group). SETD7 emerged as the most differentially expressed methyltransferase. To determine its functional role, cardiomyocyte-specific SETD7 knockout mice (c-SETD7⁻/⁻) and control littermates (SETD7fl/fl) were subjected to high-fat diet plus L-NAME for 15 weeks to induce obHFpEF. Cardiac structure and function were assessed by echocardiography and treadmill testing. ChIP-Seq was performed to map genome-wide H3K4me1 occupancy. Gain- and loss-of-function experiments were conducted in neonatal rat ventricular myocytes (NRVMs) exposed to palmitic acid (200 µM, 48h). Pharmacological SETD7 inhibition with (R)-PFI-2 was tested in skinned cardiomyocytes isolated from obHFpEF patients. Results SETD7 expression was significantly upregulated in myocardial samples from obHFpEF patients compared to controls. ChIP-Seq analysis revealed a redistribution and enrichment of the SETD7-dependent chromatin mark H3K4me1 at promoters of metabolic genes, prominently at the locus of hydroxy-methyl glutrayl co-synthase 2 (HMGCS2), a key regulator of ketogenesis. HMGCS2 expression was markedly increased in HFpEF hearts and correlated with enhanced H3K4me1 promoter occupancy, indicating epigenetic activation of ketogenesis. In vivo, cardiomyocyte-specific deletion of SETD7 protected against LV hypertrophy, diastolic dysfunction, pulmonary congestion, and exercise intolerance (Fig 1). At the molecular level, SETD7 ablation reduced H3K4me1 enrichment at the HMGCS2 promoter and normalized HMGCS2 expression, indicating direct epigenetic control. In cultured cardiomyocytes exposed to lipotoxic stress, SETD7 overexpression increased H3K4me1 deposition and induced HMGCS2 transcription, whereas SETD7 inhibition or genetic silencing suppressed HMGCS2 expression and attenuated metabolic stress signatures. Importantly, selective pharmacological inhibition of SETD7 reduced passive stiffness in skinned cardiomyocytes from obHFpEF patients, supporting translational relevance. Conclusions Targeting the SETD7–HMGCS2 axis may contribute to rescue the cardiometabolic HFpEF phenotype.