Transcriptome changes in human PSC-derived cardiomyocytes induced by doxorubicin II
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE255505 | GEO | 2026/02/08
REPOSITORIES: GEO
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Project description:Doxorubicin (DOX) is one of the most effective chemotherapeutic agents for various types of cancers. However, DOX often causes cardiotoxicity referred to as DOX-induced cardiomyopathy (DIC). Despite extensive research aimed at identifying therapeutic targets for DIC, only a limited number of effective treatments are available. In this study, we identified a member of the STE20 kinase family, thousand and one amino acid protein kinase 1 (TAOK1) as a potential regulator for DOX-induced cardiomyocyte death using a kinome-wide CRISPR gene knockout screen in human cardiomyocytes derived from pluripotent stem cells (hPSC-CMs). TAOK1 suppression improved DOX-induced cardiomyocyte dysfunction in hPSC-CMs and rescued cardiac function in a DIC mouse model. Mechanistically, we found that TAOK1 regulated p38 MAPK-mediated cardiomyocyte apoptosis induced by DOX. Our results indicate TAOK1 as a promising therapeutic strategy for treating DIC in cancer patients, and highlight the advantage of hPSC-CMs as a platform to study drug-induced cardiotoxicity.
2026-02-08 | GSE255504 | GEO
Project description:<p>Abstract</p><p>Background Doxorubicin (DOX), an anthracycline chemotherapeutic agent, is widely used for treating various malignancies. However, its clinical application is limited by dose-dependent cardiotoxicity (DOX-induced cardiotoxicity, DIC). Recent studies have shown that the gut microbiota and its metabolites may be involved in the occurrence and development of cardiovascular diseases through the 'gut-microbiota-heart axis'. Especially，doxorubicin may affect the structure and function of the gut microbiota due to its potential antimicrobial properties and its gut-damaging side effects, but the molecular mechanisms through which gut microbiota affects DIC remain poorly understood.</p><p>Results The results of 16S rRNA gene amplicon sequencing of fecal samples showed that the gut microbiota structure of the C57BL/6 DIC model mice changed. The depletion of gut microbiota by antibiotics partially improved DIC. Fecal microbiota transplantation (FMT) from DOX-treated donors impaired cardiac structure and function in recipient mice. Conversely, control-donor FMT significantly alleviated DOX-induced cardiac dysfunction, whether co-administered or given post-modeling. Mechanistically, we analyzed the metabolomics of fecal samples from mice after DOX administration and identified butyric acid (BA) as a key metabolite. Further experiments have shown that after BA treatment, the fatty acid oxidation levels impaired by DOX was restored meanwhile the glycolysis was inhibited. Besides, it was preliminarily confirmed that this metabolic alteration affects 4-hydroxynonenal (4HNE) and autophagy levels, which in turn affects DIC.</p><p>Conclusions The gut microbiota-butyrate axis restores fatty acid oxidation and normalizes glycolytic activity, further enhancing 4-HNE-mediated autophagy as a therapeutic strategy against DIC.</p><p>Keywords Doxorubicin, Gut microbiota, Cardiotoxicity, Butyric acid</p>
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Project description:The clinical application of anthracyclines such as doxorubicin (DOX) is limited due to their cardiotoxicity. N6-methyladenosine (m6A) plays an essential role in numerous biological processes. However, the roles of m6A and m6A demethylase ALKBH5 in DOX-induced cardiotoxicity (DIC) remain unclear. In this research, DIC models were constructed using Alkbh5-knockout (KO), Alkbh5-knockin (KI), and Alkbh5-myocardial-specific knockout (ALKBH5flox/flox, αMyHC-Cre) mice. Cardiac function and DOX-mediated signal transduction were investigated. As a result, both Alkbh5 whole-body KO and myocardial-specific KO mice had increased mortality, decreased cardiac function, and aggravated DIC injury with severe myocardial mitochondrial damage. Conversely, ALKBH5 overexpression alleviated DOX-mediated mitochondrial injury, increased survival, and improved myocardial function. Mechanistically, ALKBH5 regulated the expression of Rasal3 in an m6A-dependent manner through posttranscriptional mRNA regulation and reduced Rasal3 mRNA stability, thus activating RAS3, inhibiting apoptosis through the RAS/RAF/ERK signaling pathway, and alleviating DIC injury. These findings indicate the potential therapeutic effect of ALKBH5 on DIC.
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Project description:Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anti-cancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for explore the inter-individual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intra- individual variability of iPSC-CM-related assays and presented a practical approach for using donor-specific iPSC-CMs to predict personalized doxorubicin (DOX)-induced cardiotoxicity (DIC) prior to chemotherapy. Our findings demonstrated that donor-specific iPSC-CMs exhibited greater line-to-line variability than the intra-individual variability in impedance cytotoxicity and transcriptome assays. The variable and dose-dependent cytotoxic responses of iPSC-CMs resembled those observed in clinical practice, and largely replicated the reported mechanisms of DIC. By categorizing iPSC-CMs into DOX-resistant and DOX-sensitive cell lines based on their phenotypic reactions to DOX, we found that the sensitivity of donor-specific iPSC-CMs to DOX may predict in vivo DIC risk. Furthermore, we assessed the limitations of the model for identification of potential genetic/molecular biomarker and pinpointed a differentially expressed gene, DND microRNA-mediated repression inhibitor 1 (DND1), between the DOX-resistant and DOX-sensitive iPSC-CMs. We also discussed the selection of DOX dose and exposure duration for inter-individual variability of DIC assessment. Our results support the utility of donor-specific iPSC-CMs in assessing inter-individual difference and enabling personalized cardiotoxicity prediction. Further studies will encompass a large panel of donor-specific iPSC-CMs to investigate the role of the DND1 and known DIC genetic variants, and to identify potential novel molecular and genetic biomarkers for predicting DOX and other oncology drug-induced cardiotoxicity.
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Project description:The chemotherapeutic doxorubicin (DOX) detrimentally impacts the heart during cancer treatment. This necessitates development of non-cardiotoxic delivery systems that retain DOX anticancer efficacy. We utilized human induced pluripotent stem cell-derived multi-lineage cardiac spheroids (hiPSC-CSs) to compare the anticancer efficacy and reduced cardiotoxicity of single protein encapsulated doxorubicin (SPEDOX-6), to standard unformulated (UF) DOX using RNA-sequencing. The cardiac spheroids are comprised of hiPSC-derived cardiomyocytes (hiPSC-CMs), hiPSC-derived endothelial cells (ECs), and hiPSC-derived cardiac fibroblasts (CFs) at an 8:1:1 ratio.
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Project description:Doxorubicin (DOX) is considered as the major culprit in chemotherapy-induced cardiotoxicity, which limits its clinical application. Akkermansia muciniphila (AKK) shows a beneficial role as a probiotic in the treatment of metabolic syndrome. However, the changes of AKK during DIC and whether it mediates cardioprotective effects remains unclear. Cardiac transcriptomics certified by in vitro experiments demonstrated that AKK administration effectively improved mitochondrial function and alleviated DIC, by activation of PPARα/PGC1α signaling pathway. These findings provide a therapeutic strategy for DIC through supplementation with AKK.
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Project description:Doxorubicin (Dox) is an effective chemotherapeutic agent against a broad range of tumors. However, a threshold dose of doxorubicin causes an unacceptably high incidence of heart failure and limits its clinical utility. We have established two models of doxorubicin cardiotoxicity in mice: 1) in an acute model, mice are treated with 15mg/kg of doxorubicin once; 2) in a chronic model, they receive 3mg/kg weekly for the first 12 of a total of 18 weeks. Using echocardiography, we have monitored left ventricular function of the mouse hearts during treatment in chronic model and seen the expected development of dilated cardiomyopathy (DCM). Treated mice showed histological abnormalities similar to those seen in patients with doxorubicin cardiomyopathy. To investigate transcriptional regulation in these models, we used a microarray we generated with over 5000 independent cDNA clones from murine heart and skeletal muscle. We have identified genes that respond to doxorubicin exposure in both model systems, and confirmed these results using real-time PCR. In the acute model, a set of genes is regulated early and rapidly returns to baseline levels, consistent with the half-life of doxorubicin. In the chronic model, which mimics the clinical situation much more closely, we identified dysregulated genes that implicate specific mechanisms of cardiac toxicity and may serve as biomarkers of doxorubicin induced dilated cardiomyopathy. Keywords: time course
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Project description:Doxorubicin (DOX), an effective chemotherapeutic drug for various cancers, has been demonstrated to induce cardiovascular toxicity in cancer survivors. Endothelial cell (EC) dysfunction is recognized to play a critical role in the onset and severity of cardiotoxicity associated with DOX. Transcription factor EB (TFEB), a master autophagy regulator, regulates cardiovascular homeostasis. In the present study, we aimed to test whether endothelial TFEB protects against EC damage after DOX treatment.
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Project description:Doxorubicin is a widely used anti-cancer drug, and its toxicological effects on healthy tissues, especially the heart, remains challenging in therapy. To explore the potential targets that ameliorate doxorubicin-induced cardiotoxicity (DIC), we aimed to investigate the role that macrophages play in the DIC development. Senescence of RAW264.7 cells was induced through doxorubicin administration in the experiment, and the transcription of secretory components was analyzed in this study.
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