ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Stem Cell Research
This article is part of the Research TopicAdvancements in Stem Cell Differentiation and Disease ApplicationsView all 12 articles
Doxorubicin induces cardiotoxicity by enhancing autophagy via mTOR signaling in human pluripotent stem celliPSC-and hESC-derived cardiomyocytes
Provisionally accepted
- 1Zhejiang Sci-Tech University, Hangzhou, China
- 2Hangzhou Biaomo Biosciences Co., Ltd., Hangzhou, China
- 3Asia Stem Cell Therapies Co., Limited, Shanghai, China
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Doxorubicin (DOX) is a highly effective anti-cancer drug, but its clinical applications are limited by its cardiotoxicity. The mechanisms underlying doxorubicin-induced cardiotoxicity (DIC) remain incompletely understood. Human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) offer an advanced platform for investigating DIC, as they accurately recapitulate human cardiac physiology and pathology. However, the roles and mechanisms of DIC in hiPSC-CMs and hESC-CMs, especially regarding autophagy dynamics and regulation, are still not well-defined. In this study, we evaluated the effects of DOX on hiPSC-CMs and hESC-CMs, and investigated the underlying mechanisms of DIC. Our findings revealed that DOX reduced cell viability and induced apoptosis in hiPSC-CMs and hESC-CMs. Additionally, DOX caused an increase in reactive oxygen species production and DNA damage. Furthermore, DOX significantly upregulated autophagy, confirmed by the accumulation of autophagosomes and autolysosomes, and an increase in the LC3-II/LC3-I ratio. Autophagy flux assays showed that DOX induced autophagy in a time-dependent manner. The autophagy mediated by DOX was partially attenuated by 3-methyladenine (3-MA). Moreover, this activation is due to mTOR signaling inhibition. The down-regulation of mTOR signaling by rapamycin (RAPA) increased cell death of hESC-CMs. Taken together, our study uncovered the multifaceted effects of DOX on hiPSC-CMs and hESC-CMs, revealing a shared mechanism in which DOX enhances autophagy via inhibition of the mTOR signaling pathway. Interestingly, minor variations in injury severity and cellular sensitivity are observed between these two models. These findings reveal key insights into DIC pathogenesis and suggest that autophagy modulation may be a promising therapy.
Keywords: Doxorubicin, cardiomyocytes, Autophagy, MTOR signaling, Human Induced Pluripotent Stem Cells, human embryonic stem cells
Received: 22 Apr 2025; Accepted: 04 Nov 2025.
Copyright: © 2025 Ke, Wang, Yang, Ji, Qi and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Nianmin Qi, drqi@163.com
Yuehong Wu, wuyuehong2003@163.com
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