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| Item Type: | Article |
|---|---|
| Title: | HDAC inhibition via suberoylanilide hydroxamic acid ameliorates doxorubicin-induced cardiotoxicity |
| Creators: |
Eksi, Benay, Finke, Daniel, Michel, Synje, Brauer, Jannek, Heckmann, Markus B., Valadan, Mohsen, Schanze, Leonard M., Sunder, Vighnesh, Steimel, Kevin, Burhenne, Jürgen, Seeger, Timon, Katus, Hugo A., Frey, Norbert, Backs, Johannes  ORCID: https://orcid.org/0000-0002-2322-2699 and Lehmann, Lorenz H.
|
| Abstract: | Anthracycline-induced cardiotoxicity remains a major limitation of cancer therapy, and effective preventive strategies are lacking. Topoisomerase IIb has been implicated as a central driver of this toxicity, suggesting that epigenetic regulators may interfere with the pathological cardiac response. Here, we show that doxorubicin promotes topoisomerase IIb accumulation at cardiomyocyte-specific gene promoters (e.g., Actc1, Myl2, and Myh7) overlapping myocyte enhancer factor 2 binding sites and enhances myocyte enhancer factor 2 -dependent transcription. This response is attenuated by the pan-histone deacetylase inhibitor suberoylanilide hydroxamic acid. Suberoylanilide hydroxamic acid -mediated cardioprotection requires class IIa histone deacetylases, as genetic loss of HDAC4 abolishes its effect. Mechanistically, suberoylanilide hydroxamic acid induces acetylation of the chaperone 14-3-3, disrupting its interaction with HDAC4/5, promoting their nuclear accumulation, and repressing myocyte enhancer factor 2 - driven transcription. In vivo, suberoylanilide hydroxamic acid mitigates doxorubicin-induced cardiotoxicity. These findings identify histone deacetylase inhibition as a cardioprotective repurposing strategy and reveal a mechanistic link between epigenetic regulation and anthracycline-associated cardiotoxicity. |
| Keywords: | Acetylation, Cardiac Myocytes, Cardiotoxicity, Doxorubicin, Genetic Epigenesis, Genetic Promoter Regions, Histone Deacetylase Inhibitors, Histone Deacetylases, Hydroxamic Acids, MEF2 Transcription Factors, Repressor Proteins, Substances, Type II DNA Topoisomerases, Vorinostat, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 17 |
| Number: | 1 |
| Page Range: | 9505 |
| Date: | 4 September 2026 |
| Official Publication: | https://doi.org/10.1038/s41467-026-77428-w |
| PubMed: | View item in PubMed |
| Related to: |
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