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March 15, 2026European Journal of Heart Failure

Into the heart of anthracycline cardiotoxicity: single-cell insights from early cardiomyocyte stress to multicellular remodeling

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Why the study?

Preventive strategies against anthracycline cardiotoxicity are hindered by an incomplete understanding of the earliest molecular and cellular mechanisms preceding functional decline.

Does GASK1B silencing prevent doxorubicin-induced cardiotoxicity in preclinical models?

Population

Mice, zebrafish, neonatal mouse cardiomyocytes, hiPSC-CMs, and 17 human heart samples

Comparison

Doxorubicin treatment vs control, and GASK1B silencing

Design

Preclinical transcriptomic and functional validation study

Follow-up

3 days and 6 weeks

Key result

GASK1B was up-regulated in doxorubicin-induced cardiotoxic hearts and silencing it preserved cardiomyocyte function and reduced damage in multiple models.

Authors

MMMarco MergiottiYQY QinJFJens Van fraeyenhove

Discussion

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Overview

Should not change clinical practice; extends preclinical evidence for GASK1B as therapeutic target in anthracycline cardiotoxicity.

Key Points

  • The aim is to understand the molecular and cellular mechanisms underlying doxorubicin-induced cardiotoxicity and identify potential targets for cardioprotection.
  • Doxorubicin treatment (4 mg/kg weekly for three weeks) in mice
  • Single-nucleus RNA sequencing to analyze cardiac tissues at different time points
  • Bioinformatic analyses (Milo, CellChat, trajectory inference) for changes in cell types
  • Validation in zebrafish, mouse cardiomyocytes, and human iPSC-derived cardiomyocytes
  • Identified eight major cardiac cell types through transcriptomic profiling
  • Doxorubicin primarily affects cardiomyocytes, fibroblasts, and myeloid cells
  • Observed an intermediate transcriptional state in cardiomyocytes enriched in TGFB2 signaling
  • GASK1B was found up-regulated in cardiotoxic hearts and linked to cardiac injury across species

Structured PICO

Does GASK1B silencing prevent doxorubicin-induced cardiotoxicity in preclinical models?

P
Population
Mice, zebrafish, neonatal mouse cardiomyocytes, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), and 17 human heart samples (control and anthracycline-cardiotoxic).
I
Intervention
Doxorubicin (4 mg/kg weekly for three weeks in mice) and GASK1B silencing.
C
Comparator
Control (untreated) samples.
O
Outcome
Early and late transcriptional programs driving doxorubicin-induced cardiotoxicity and identification of cardioprotective targets.surrogate

GASK1B is identified as a novel, conserved mediator of anthracycline-induced cardiotoxicity, and its silencing offers a potential therapeutic target for cardioprotection.

Cite This Study

Mergiotti et al. (2026) studied this question. GASK1B was up-regulated in doxorubicin-induced cardiotoxic hearts and silencing it preserved cardiomyocyte function and reduced damage in multiple models.

synapsesocial.com/papers/69b64c33b42794e3e660da47https://doi.org/10.1093/ejhf/xuag034.009
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