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

Clicks: 1
ID: 323389
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal

Ranked #221 of 282 articles by views in European heart journal supplements : journal of the European Society of Cardiology

Most read Least read

Bar heights use a square-root scale. Only the 120 most-read articles are drawn; the journal has 282 in total.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
Abstract Background Anthracycline-induced cardiotoxicity remains a major limitation of cancer therapy and effective preventive strategies are lacking. Topoisomerase IIb (Topo IIb) has been implicated as a central driver of anthracycline cardiotoxicity, suggesting that epigenetic regulators may modulate the toxic response. While histone deacetylase (HDAC) inhibitors protect against pathological cardiac remodelling in pressure overload, their role in anthracycline cardiotoxicity remains unclear. Purpose Given the key role of MEF2 in pathological cardiac remodelling, we investigated whether the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) protects against doxorubicin (Doxo)-induced cardiotoxicity by promoting HDAC4-dependent repression of MEF2 signalling. Methods Mechanistic studies evaluated 14-3-3 acetylation, 14-3-3–HDAC4 interaction and HDAC4 subcellular localisation. MEF2 transcriptional activity in cardiomyocytes was assessed with and without SAHA. In vivo, mice received Doxo (3 mg/kg, eight injections over two weeks) with or without SAHA. Long-term effects were assessed nine weeks after the last injection by echocardiography and qPCR of the MEF2 target gene Myh7. Selective class IIa HDAC inhibition was tested using TMP195 and genetic loss-of-function was evaluated in conditional cardiomyocyte-specific HDAC4-deficient mice. Statistical analysis used one-way ANOVA with Bonferroni correction where p<0.05 was considered significant. Results SAHA induced 14-3-3 hyperacetylation, disrupted the 14-3-3–HDAC4 interaction and promoted nuclear accumulation of HDAC4, thereby suppressing MEF2 activation. In vivo, Doxo reduced left ventricular ejection fraction (LVEF), whereas SAHA co-treatment preserved function (Control 50.3 ± 3.1%, n=12 vs Doxo 43.0 ± 3.4% vs Doxo+SAHA 50.6 ± 7.4%, p>0.05) and blunted Doxo-induced pathological gene induction, including Myh7. In contrast, the selective class IIa HDAC inhibitor TMP195 did not improve Doxo-induced dysfunction (Control 49.1 ± 7.8%, n=12 vs Doxo 40.8 ± 4.8%, n=10, p<0.05 vs Doxo+TMP195 37.1 ± 6.2%, n=6, p<0.05) and failed to normalise Myh7. Cardiomyocyte-specific HDAC4-deficient mice showed impaired cardiac function after Doxo and Doxo+SAHA (Control 51.7 ± 5.4%, n=5 vs Doxo 34.9 ± 5.4%, n=4, p<0.05 vs Doxo+SAHA 37.9 ± 3.9%, n=4, p<0.05), indicating that HDAC4 is required for SAHA efficacy. Conclusion Together, our findings identify pan-HDAC inhibition as a cardioprotective repurposing strategy for anthracycline treatment and reveal a mechanistic link between 14-3-3 acetylation, nuclear accumulation of HDAC4 and repression of MEF2-driven pathological cardiac remodelling.
Reference Key
openalex_W7172278350 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors B Eksi, D Finke, S Michel, J Brauer, M B Heckmann, M Valadan, L Schanze, V Sunder, H A Katus, N Frey, J Backs, L H Lehmann
Journal European heart journal supplements : journal of the European Society of Cardiology
Year 2026
DOI
10.1093/eurheartjsupp/suag097.227
URL
https://doi.org/10.1093/eurheartjsupp/suag097.227
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.