Background: Impaired energy metabolism in the heart is critical in the development of cardiac hypertrophy and failure. Src-associated in mitosis 68 kDa (Sam68) is a member of the signal transducer and activator of RNA (STAR) protein family, and its role in cardiac energy metabolism is undefined. Methods: We assessed Sam68 expression in human myopathic and failing hearts. We also generated mice with cardiomyocyte-specific Sam68 deletion or overexpression and subjected them to angiotensin II infusion or transverse aortic constriction (TAC) surgery to induce pathological cardiac hypertrophy. Mechanistic studies were performed using RNA-seq, metabolomics, and immunoprecipitation analyses. Results: Sam68 expression was significantly elevated in cardiomyocytes of human myopathic and failing hearts. Deletion of Sam68 in adult mouse cardiomyocytes prevented angiotensin II- and TAC-induced cardiac hypertrophy. Conversely, AAV9-mediated overexpression of Sam68 in cardiomyocyte exacerbated cardiac hypertrophy and failure. RNA-seq and metabolomic analyses showed that Sam68 deficiency led to a marked downregulation of pyruvate dehydrogenase kinase 4 (PDK4), which was associated with enhanced cardiac glucose oxidation and oxidative phosphorylation. Mechanistically, Sam68 directly interacts with STAT3, promoting its phosphorylation and nuclear translocation via Src signaling, thereby enhancing PDK4 transcription. Pharmacological inhibition of the Sam68-Src interaction using a specific peptidomimetic molecule mitigated pathological cardiac hypertrophy by attenuating STAT3 phosphorylation and restoring glucose oxidation. Additionally, the Sam68/STAT3/PDK4 signaling axis was significantly unregulated in patients with heart failure. Conclusions: Our findings reveal a novel role of Sam68 in regulating cardiac glucose oxidation, highlighting the potential therapeutic targeting of Sam68 for managing cardiac hypertrophy and heart failure.

The authors have declared no competing interest.

This is not a clinical trial.

This work was financially supported by the National Natural Science Foundation of China (grant numbers #82350710224 to G.Q., #82300285 to C.H., #82400322 to J.A.), Shenzhen Medical Research Fund (#B2302025 to G.Q.), Guangdong Natural Science Foundation (#2414050005637 to C.H.), China Postdoctoral Science Foundation (#2023TQ0149 to J.A.), China Postdoctoral Fellowship Program (GZC20231039 to J.A.), and a startup fund from Southern University of Science and Technology awarded to G.Q.

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The study protocol for human heart samples is approved by the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (Approval number: UHCT-IEC-SOP-016-03-01). Written informed consent was obtained from all heart donors and transplant patients.

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The majority of the data supporting the findings are included in this report. Additional data can be obtained from the corresponding author upon reasonable request.