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Lookup NU author(s): Laura BoothORCiD, Dr Rachael RedgraveORCiD, Dr Maria Camacho EncinaORCiD, Dr Marco Trevisan, Dr Laura WalkerORCiD, Dr Gailing Ma, Lily Mathison, Dr Simon Tual-ChalotORCiD, Dr Jason GillORCiD, Professor Viktor KorolchukORCiD, Professor Gavin RichardsonORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Introduction Anthracycline chemotherapies are broad-spectrum anticancer agents, essential for treating haematological malignancies, sarcoma and breast cancer. However, these therapies have long been associated with late-onset cardiotoxicity, which manifests many years after treatment conclusion in up to 5-10% of patients, and can culminate in fulminant heart failure. The induction of cellular senescence in the heart has been explored as a contributing mechanism to anthracycline-induced cardiotoxicity (AIC) – senescence being classically defined as irreversible exit from the cell cycle accompanied by a pro-inflammatory senescence-associated secretory phenotype (SASP). Recent studies show that cardiomyocytes (CMs), though post-mitotic, can acquire a senescent phenotype via natural ageing or stress, but the causal link between this cellular fate and disease is not well understood. We aimed to explore whether a sublethal, clinically relevant dose of anthracycline (doxorubicin, DOX) could induce senescence in cardiomyocytes in vitro, and to broadly characterize their phenotype, using this as a basis for the development of novel therapeutics.Methods and Results AC16 CMs and induced pluripotent stem cell (iPSC)-derived CMs were exposed to 500 nM DOX for 3 hours, then allowed to recover for 10 days in culture. At day 10, both models showed significant upregulation of classical senescence-associated transcript CDKN1A (5-fold and 3-fold, respectively), of novel senescence transcript PURPL (5-fold and 2-fold), and of cardiovascular stress marker GDF15 (26-fold and 7-fold). Classical marker senescence-associated beta galactosidase (SA-β-Gal) was also increased 5-fold in AC16s. Bulk RNA-seq analysis of iPSC-CMs 10 days post-DOX showed robust senescence-associated transcriptomic changes, according to externally validated gene panels (e.g. SenMayo).Senescent cells are known to display increased mitochondrial mass, which can be caused by dampened mitochondrial turnover via autophagy. Furthermore, DOX is known to directly damage mitochondria, upon which contractile cardiomyocytes are especially reliant given their particularly high energy demands. Indeed, immunofluorescent imaging showed the mitochondrial network footprint of DOX-exposed AC16s was significantly larger than control (23-fold) and had a significantly lower mean network branch length (1.4 µm vs 1.8 µm), which could suggest dysregulated mitochondrial fission/fusion dynamics.We have previously shown that stimulating p62-dependent mitophagy using a novel small molecule ‘SQ-1’ can rescue mitophagy defects in aged, senescent fibroblasts and reduce mitochondrial mass (PMID 38897197). Bulk RNA-seq analysis of iPSC-CMs ‘primed’ with SQ-1 before DOX exposure showed robust rescue in ~10% of genes impacted by exposure: these genes broadly fall into mitochondrial and metabolic homeostasis (e.g. ETNPPL, BCO2, SELENBP1 downregulated with DOX, upregulated with SQ-1) and injury, inflammation and maladaptive remodelling (e.g. GDF15, SERPINE1, COL4A upregulated with DOX, downregulated with SQ-1). Strong positive enrichment of the SenMayo gene panel (NES = 2.00) in DOX-exposed CMs vs control is also reversed in SQ-1+DOX-exposed CMs vs DOX-exposed CMs (NES = -1.81).Conclusions and Implications Given the established contribution of senescence to myocardial remodelling in other cardiovascular disease (CVD) settings (e.g. myocardial infarction, age-associated CVD), these data suggest that activation of mitophagy is a viable strategy to mitigate CM senescence and consequent remodelling, with the potential to improve clinical outcomes. Therefore, the aforementioned targets, amongst others, will form the basis of further functional work to elucidate how SQ-1 modulates the DOX-induced CM senescent phenotype, and how this modulation may contribute to alleviating anthracycline-induced cardiotoxicity mechanisms.
Author(s): Booth LK, Redgrave RE, Camacho-Encina M, Trevisan-Herraz M, Walker L, Ma G, Mathison L, Tual-Chalot ST, Gill J, Korolchuk V, Richardson GD
Publication type: Article
Publication status: Published
Journal: Heart
Year: 2026
Volume: 112
Issue: Suppl 1
Print publication date: 09/06/2026
Online publication date: 09/06/2026
Acceptance date: 01/05/2026
Date deposited: 01/07/2026
ISSN (print): 1355-6037
ISSN (electronic): 1468-201X
Publisher: BMJ Group
URL: https://doi.org/10.1136/heartjnl-2026-BCS.274
DOI: 10.1136/heartjnl-2026-BCS.274
ePrints DOI: 10.57711/3ne9-4f62
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