Abstract 4344599: Converging Mechanisms in Divergent Cardiomyopathies: FSCN1 as a Druggable Epigenetic-Mitochondrial Target in Heart Failure

Abstract

Background: Heart failure (HF) is the final common outcome of diverse cardiomyopathies (CMys), including dilated (DCM), ischemic (ICM), and hypertrophic (HCM), and remains a major cause of morbidity and mortality. Despite distinct etiologies and presentations, their molecular mechanisms may converge. Identifying a shared, druggable molecular driver could enable new, broadly applicable therapies. Methods: We analyzed RNA-seq and single-cell RNA-seq data from human left ventricular tissue in DCM, ICM, and HCM compared to healthy controls. Shared differentially expressed genes (DEGs) were cross-referenced with gene-disease correlation scores to identify common upregulated drivers. FSCN1 emerged as the top candidate and was validated via overexpression (gain-of-function, GOF), genetic knockdown (loss-of-function, LOF), and pharmacologic inhibition (HY-B1490) in primary cardiomyocytes and murine HF models, including transverse aortic constriction (TAC), myocardial infarction (MI), and MHC-F764L DCM mice. RNA-seq and proteomics were performed to identify regulated pathways and interacting proteins. Mitochondrial function was evaluated using OXPHOS Western blotting, Seahorse assays, electron microscopy, and MitoSOX staining. A KDM5B inhibitor (TK-129) was tested in cardiomyocytes and FSCN1-overexpressing mouse hearts. Results: A total of 244 DEGs were shared across CMys. FSCN1 was consistently upregulated (>1.5-fold, adj.p<0.01) and strongly correlated with disease (p<4.65E-116). Pseudotime analysis revealed elevated FSCN1 expression in cardiomyocytes at later disease stages, suggesting a role in progression. FSCN1 overexpression worsened HF (n=6–9, p=0.0004), while both genetic and pharmacologic inhibition preserved function (n=5–8, all p<0.05). RNA-seq showed suppression of mitochondrial pathways in FSCN1-overexpressing hearts. FSCN1 GOF reduced mitochondrial gene expression and respiration, and induced ultrastructural damage, which was reversed by LOF or inhibition. Proteomics identified KDM5B as an FSCN1 interactor. FSCN1 increased nuclear KDM5B, reduced H3K4me3, and suppressed mitochondrial regulator PPARGC1A. These effects were reversed by KDM5B inhibition. Conclusion: FSCN1 is a common driver in diverse CMys and HF. It contributes to mitochondrial dysfunction via nuclear epigenetic remodeling. Targeting FSCN1 genetically or pharmacologically preserves mitochondrial integrity and cardiac function, supporting its potential as a therapeutic target in heart failure.