Hepatic Ketogenesis Attenuates Cardiac Hypertrophy via Metabolic Reprogramming

Abstract Background Heart failure with preserved ejection fraction (HfpEF) is increasingly recognized as a multisystem disorder linked to the cardiovascular-kidney-metabolic (CKM) syndrome. While the falling heart undergoes metabolic reprogramming, the interorgan crosstalk regulating myocardial substrate preference in HFpEF remains elusive. We aimed to clarify the role of systemic and local ketogenesis in the pathogenesis of cardiac hypertrophy and HFpEF. Methods A mouse model of HFpEF was employed using a high-fat diet combined with NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME). Cardiac hypertrophy and systemic metabolic profiling including ketogenesis were evaluated. To dissect the role of site-specific ketogenesis, we generated inducible cardiomyocyte-specific ( Hmgcs2 ΔiCM ) and hepatocyte-specific ( Hmgcs2 ΔHep ) knockout mice of HMG-CoA synthase 2 ( Hmgcs2 ), deficient in the rate-limiting enzyme for ketogenesis. Cardiomyocyte -specific nuclei were isolated for transcriptomic (RNA-seq) and in vitro assays in H9C2 cells were used to elucidate molecular mechanisms. Results The HFpEF model successfully exhibited diastolic dysfunction, impaired exercise capacity and cardiac hypertrophy with elevated circulating ketone body concentration. Myocardial metabolomics and snRNA-seq identified a profound metabolic shift characterized by the accumulation of long-chain fatty acids and Krebs cycle intermediates, coupled with the transcriptional downregulation of insulin signaling and fatty acid degradation pathways. Although circulating ketone body level was upregulated, Hmgcs2 ΔiCM mice showed no exacerbation of the HFpEF phenotype. In contrast, Hmgcs2 ΔHep mice exhibited significantly aggravated cardiac hypertrophy (HW/TL; Hmgcs2 flox : 7.41 ± 0.87: Hmgcs2 ΔHep : 8.29 ± 0.73; p = 0.0154). Mechanistically, hepatic ketogenesis was required to maintain circulating beta-hydroxybutyrate (BHB) levels, which directly modulated cardiomyocyte metabolism. BHB acted as a metabolic signal to dampen fatty acid overload and facilitate glucose utilization. Conclusions Our study identifies a critical "liver-heart axis" where hepatic ketogenesis serves as an essential regulator of myocardial metabolic resilience. Impaired hepatic ketogenesis creates a metabolic mismatch that drives pathological cardiac remodeling. These findings highlight the liver as a therapeutic target within the CKM syndrome framework, suggesting that restoring the hepato-cardiac metabolic bridge may ameliorate HFpEF progression. What is New? This study identifies a novel liver–adipose–heart axis that governs myocardial metabolic resilience during the development of heart failure with preserved ejection fraction (HFpEF). We demonstrate that while both the liver and heart upregulate ketogenesis under metabolic stress, only hepatic ketogenesis—and not cardiac-intrinsic ketogenesis—is essential for mitigating pathological cardiac remodeling. Mechanistically, liver-derived β -hydroxybutyrate acts as a critical endocrine signal that dampens fatty acid oxidation and facilitates myocardial glucose utilization. What Are the Clinical Implications? Our findings highlight the liver as a central therapeutic target within the cardiovascular–kidney–metabolic (CKM) syndrome framework, where hepatic metabolic failure directly drives cardiac dysfunction. Restoring the hepato-cardiac metabolic bridge, through either hepatic-targeted therapies or ketone body supplementation, represents a promising strategy to enhance myocardial metabolic flexibility and ameliorate HfpEF in patients with multi-organ metabolic disorders.