What question did this study set out to answer?

To determine the molecular mechanisms underlying delayed and progressive cardiac endothelial dysfunction following the completion of doxorubicin chemotherapy.

January 10, 2026Cardio-OncologyOpen Access

Sustained mesenchymal reprogramming of endothelial cells after completion of chemotherapy

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Key result

ALK4/5/7 kinase inhibitor SB431542 blocks endothelial reprogramming and increased permeability after doxorubicin washout.

Why the study?

Cardiac damage from doxorubicin typically progresses after chemotherapy completion, but the nature of this delayed deterioration remains not understood.

Does ALK4/5/7 receptor kinase inhibition with SB431542 prevent doxorubicin-induced endothelial-to-mesenchymal reprogramming and barrier dysfunction during chemotherapy washout in preclinical models?

Key Points

To determine the molecular mechanisms underlying delayed and progressive cardiac endothelial dysfunction following the completion of doxorubicin chemotherapy.
Evaluated endothelial responses to transient drug exposure using a 48-h doxorubicin treatment and 48-h washout model in cultured endothelial cells and an in vivo mouse model with 5 mg/kg intravenous injection (n=3 per group; control n=2).
Mapped Smad3 binding sites and canonical TGF-β/activin pathway activation using ChIP sequencing, RNA transcriptomics, CAGA12-luciferase reporter assays, and Smad2/3 phosphorylation immunoblots.
Tested rescue of endothelial phenotypes during washout using the selective ALK4/5/7 receptor kinase inhibitor SB431542.
Doxorubicin washout enhanced Smad2 and Smad3 phosphorylation and elevated expression of ligand transcripts, including Tgfb2, Inhba, and Inhbb.
Washout induced sustained mesenchymal reprogramming, marked by upregulated fibroblastic and smooth muscle transcripts, cytoskeletal remodeling, and increased monolayer permeability.
Treatment with SB431542 during washout blocked mesenchymal marker expression, prevented fibronectin production, and reversed endothelial barrier leakage.

Structured PICO

Does ALK4/5/7 receptor kinase inhibition with SB431542 prevent doxorubicin-induced endothelial-to-mesenchymal reprogramming and barrier dysfunction during chemotherapy washout in preclinical models?

Population

Preclinical models: 8 to 11-week-old male and female C57BL/6J mice, 10 to 15-week-old male B6;129 mice, and cultured human endothelial cells (HUVEC and HCMVEC).

Intervention

Doxorubicin (Dox) treatment (in vivo: 5 mg/kg IV for 4 injections; in vitro: 16 nM) followed by washout, with or without ALK4/5/7 receptor kinase inhibitor SB431542 (1 µM).

Comparator

Vehicle (saline) for in vivo models; untreated or Dox-only treated cells for in vitro models.

Outcome

Endothelial-to-mesenchymal reprogramming, Smad2/3 phosphorylation, and endothelial barrier function (monolayer permeability) during Dox washout.surrogate

Inhibition of the TGF-β/activin pathway prevents delayed endothelial-to-mesenchymal reprogramming and barrier dysfunction following doxorubicin exposure, offering a potential mechanistic target for anthracycline-induced cardiotoxicity.

Discussion

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Implication

May support ALK4/5/7 inhibition to prevent delayed doxorubicin endothelial dysfunction; hypothesis-generating in this animal model.

Cite This Study

Sjostrom et al. (2025) studied this question. Doxorubicin washout sustained mesenchymal reprogramming of endothelial cells, increasing permeability, which was blocked by the ALK4/5/7 kinase inhibitor SB431542.

synapsesocial.com/papers/6963221691e05aa366cb88d6 https://doi.org/10.1186/s40959-025-00413-7

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Sustained mesenchymal reprogramming of endothelial cells after completion of chemotherapy

Key Points

Structured PICO

Discussion

Implication

Cite This Study

Sustained mesenchymal reprogramming of endothelial cells after completion of chemotherapy

Key Points

Structured PICO

Discussion

Implication

Cite This Study

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