Related Experiment Video
Updated: Jun 9, 2025
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
AMPD3 promotes doxorubicin-induced cardiomyopathy through HSP90α-mediated ferroptosis
Liting Cheng1,2, Mingxiang Zhu2,3, Xiang Xu2
1School of Medicine, Nankai University, Tianjin, China.
Abstract:
Doxorubicin (DOX), a widely used anticancer drug, can induce myocardial damage, and current treatments are limited. Our research identified AMPD3 upregulation in DOX-induced cardiotoxicity (DIC), and we hypothesized that AMPD3 may contribute to cardiac injury by regulating mitochondrial dynamics and ferroptosis. We generated AMPD3 knockout (KO) mice and AC16 cell models with AMPD3 knockdown/overexpression, using various methods to explore underlying mechanisms. AMPD3 KO mice showed improved ejection fractions and reduced myocardial injury compared to controls. Transcriptome sequencing revealed reduced HSP90AA1, HSP90B1, ACSL4, and dynamin-related protein 1 (DRP1) levels. We further demonstrated that AMPD3 interacts with HSP90α, activating DRP1, leading to mitochondrial fission, increased reactive oxygen species (ROS) release, and ACSL4-mediated ferroptosis. Our findings suggest inhibiting AMPD3 during DOX treatment may alleviate myocardial damage, highlighting mitochondrial function and ferroptosis as potential therapeutic targets for DIC.
Insights
Inhibiting AMPD3 may protect the heart from Doxorubicin-induced cardiotoxicity by preventing mitochondrial dysfunction and ferroptosis, offering new therapeutic avenues.
Area of Science:
- Biochemistry
- Cardiology
- Molecular Biology
Background:
- Doxorubicin (DOX) is a vital chemotherapy agent but causes significant myocardial damage.
- Current treatments for DOX-induced cardiotoxicity (DIC) are insufficient, necessitating novel therapeutic strategies.
Purpose of the Study:
- To investigate the role of AMPD3 in DOX-induced cardiotoxicity.
- To explore the underlying mechanisms involving mitochondrial dynamics and ferroptosis.
Main Methods:
- Generated AMPD3 knockout mice and AC16 cell models with manipulated AMPD3 expression.
- Utilized transcriptome sequencing, biochemical assays, and microscopy to analyze cellular changes.
- Investigated the interaction between AMPD3, HSP90α, and DRP1.
Main Results:
- AMPD3 knockout mice exhibited improved cardiac function and reduced injury after DOX treatment.
- AMPD3 upregulation was linked to increased mitochondrial fission, reactive oxygen species (ROS) production, and ferroptosis.
- AMPD3 was found to interact with HSP90α, activating DRP1 and promoting mitochondrial fragmentation.
Conclusions:
- AMPD3 plays a critical role in DOX-induced cardiotoxicity by regulating mitochondrial dynamics and ferroptosis.
- Inhibiting AMPD3 presents a promising therapeutic strategy to mitigate Doxorubicin-induced myocardial damage.
- Targeting mitochondrial function and ferroptosis pathways could offer new treatments for cardiotoxicity.
