GASK1B was up-regulated in doxorubicin-induced cardiotoxic hearts and silencing it preserved cardiomyocyte function and reduced damage in multiple models.
Does GASK1B silencing prevent doxorubicin-induced cardiotoxicity in preclinical models?
GASK1B is identified as a novel, conserved mediator of anthracycline-induced cardiotoxicity, and its silencing offers a potential therapeutic target for cardioprotection.
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Abstract Background Anthracycline chemotherapy remains a cornerstone in cancer treatment but is limited by dose-dependent cardiotoxicity that can progress from subclinical myocardial injury to heart failure. Preventive strategies are hindered by an incomplete understanding of the earliest molecular and cellular mechanisms that precede functional decline. Purpose To dissect the early and late transcriptional programs driving doxorubicin-induced cardiotoxicity and identify relevant targets for cardioprotection. Methods Mice were treated with doxorubicin (4 mg/kg weekly for three weeks) and hearts were collected at 3 days (early, preserved function) and 6 weeks (late, impaired function) for single-nucleus RNA sequencing (snRNAseq, ~53, 000 nuclei from 12 hearts). Bioinformatic analyses (Milo, CellChat, trajectory inference) were used to map compositional and signaling changes across cell types. Functional validation was performed in zebrafish, neonatal mouse cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Human validation was also performed by snRNA-seq from 17 hearts (6 in-house and 11 publicly available datasets) spanning control and anthracycline-cardiotoxic samples. Results Single-nucleus transcriptomic profiling identified eight major cardiac cell types. Drug2cell analysis predicted cardiomyocytes, fibroblasts and myeloid cells as the most targeted by doxorubicin, supported by differential abundance testing. At 3 days, cardiomyocytes displayed an intermediate transcriptional state (CM1Intermediate) enriched in TGFB2 signaling, predicted to mediate early communication with fibroblasts and myeloid cells. Trajectory analysis positioned CM1Intermediate as a transition linking a basal to a stressed cell state in cardiomyocytes, suggesting that early TGFB2 activation contributes to later maladaptive remodeling. By 6 weeks, a multicellular network emerged with activated fibroblasts, Trem2ʰigh macrophages and type-2 dendritic cells, reinforcing TGF-β, SPP1 and IL-1β pathways and promoting maladaptive tissue remodeling. Along the cardiomyocyte trajectory, progressive induction of Nppb, Myh7, and marked up-regulation of GASK1B, a Golgi-associated kinase not previously linked to cardiac pathology, were observed. GASK1B up-regulation was validated at transcript and protein levels in murine and human cardiotoxic hearts. Silencing GASK1B attenuated doxorubicin-induced dysfunction in zebrafish, reduced DNA damage in mouse cardiomyocytes, and preserved viability and ATP content in hiPSC-CMs. Conclusions This study delineates the temporal and multicellular architecture of anthracycline cardiotoxicity, highlighting cardiomyocyte stress responses and fibroblast–immune interactions as key pathogenic processes. GASK1B emerges as a conserved mediator of cardiotoxic injury across species, including humans, representing a promising candidate for targeted cardioprotection in cancer therapy.
Mergiotti et al. (Sun,) reported a other. GASK1B was up-regulated in doxorubicin-induced cardiotoxic hearts and silencing it preserved cardiomyocyte function and reduced damage in multiple models.