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| Item Type: | Preprint |
|---|---|
| Title: | HDAC inhibition via suberoylanilide hydroxamic acid (SAHA) ameliorates Doxorubicin-induced cardiotoxicity |
| Creators Name: | Eksi, Benay, Finke, Daniel, Michel, Synje, Brauer, Jannek, Heckmann, Markus B., Valadan, Mohsen, Schanze, Leonard M., Sunder, Vighnesh, Katus, Hugo A., Frey, Norbert, Backs, Johannes and Lehmann, Lorenz H. |
| Abstract: | 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. |
| Keywords: | Animals, Mice |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.01.12.698976 |
| Date: | 12 January 2026 |
| Official Publication: | https://doi.org/10.64898/2026.01.12.698976 |
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