HDAC inhibition via suberoylanilide hydroxamic acid (SAHA) ameliorates Doxorubicin-induced cardiotoxicity

BACKGROUND: Anthracycline-induced cardiotoxicity remains a major limitation of cancer therapy, and effective preventive strategies are lacking. Topoisomerase IIβ (Topo IIb) has been implicated as a central driver of this toxicity, suggesting that epigenetic regulators may interfere with pathological cardiac response. METHODS AND RESULTS: Here, we show that doxorubicin promotes Topo IIb accumulation at cardiomyocyte gene promoters (e.g., Actc1, Myl2, and Myh7) overlapping myocyte enhancer factor 2 (MEF2) binding sites and enhances MEF2-dependent transcription. This response is attenuated by the pan–histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA). SAHA-mediated cardioprotection requires class IIa HDACs, as genetic loss of HDAC4 abolishes its effect. Mechanistically, SAHA induces acetylation of the chaperone 14-3-3, disrupting its interaction with HDAC4/5, promoting their nuclear accumulation, and repressing MEF2-driven transcription. In vivo, SAHA mitigates doxorubicin-induced cardiotoxicity. CONCLUCION: These findings identify HDAC inhibition as a cardioprotective repurposing strategy and reveal a mechanistic link between epigenetic regulation and anthracycline-associated cardiotoxicity.