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Updated: Nov 7, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
SNX17 protects the heart from doxorubicin-induced cardiotoxicity by modulating LMOD2 degradation
Yanping Zhang1, Le Ni2, Bowen Lin2
1Department of Vascular and Cardiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract:
Anthracyclines including doxorubicin (DOX) are still the most widely used and efficacious antitumor drugs, although their cardiotoxicity is a significant cause of heart failure. Despite considerable efforts being made to minimize anthracycline-induced cardiac adverse effects, little progress has been achieved. In this study, we aimed to explore the role and underlying mechanism of SNX17 in DOX-induced cardiotoxicity. We found that SNX17 was downregulated in cardiomyocytes treated with DOX both in vitro and in vivo. DOX treatment combined with SNX17 interference worsened the damage to neonatal rat ventricular myocytes (NRVMs). Furthermore, the rats with SNX17 deficiency manifested increased susceptibility to DOX-induced cardiotoxicity (myocardial damage and fibrosis, impaired contractility and cardiac death). Mechanistic investigation revealed that SNX17 interacted with leiomodin-2 (LMOD2), a key regulator of the thin filament length in muscles, via its C-TERM domain and SNX17 deficiency exacerbated DOX-induced cardiac systolic dysfunction by promoting aberrant LMOD2 degradation through lysosomal pathway. In conclusion, these findings highlight that SNX17 plays a protective role in DOX-induced cardiotoxicity, which provides an attractive target for the prevention and treatment of anthracycline induced cardiotoxicity.
Insights
SNX17 protects against doxorubicin (DOX)-induced cardiotoxicity by stabilizing leiomodin-2 (LMOD2). SNX17 downregulation worsens heart damage, suggesting it as a therapeutic target for chemotherapy-related heart failure.
Area of Science:
- Cardiology
- Oncology
- Molecular Biology
Background:
- Anthracyclines like doxorubicin (DOX) are effective anticancer drugs but cause significant cardiotoxicity, leading to heart failure.
- Minimizing anthracycline-induced cardiac adverse effects remains a major clinical challenge with limited therapeutic progress.
Purpose of the Study:
- To investigate the role of SNX17 in doxorubicin (DOX)-induced cardiotoxicity.
- To elucidate the underlying molecular mechanisms by which SNX17 influences DOX cardiotoxicity.
Main Methods:
- Examined SNX17 expression in cardiomyocytes treated with DOX in vitro and in vivo.
- Assessed the impact of SNX17 interference and deficiency on DOX-induced cardiac damage and dysfunction in neonatal rat ventricular myocytes (NRVMs) and rats.
- Investigated the interaction between SNX17 and leiomodin-2 (LMOD2) and its role in the lysosomal degradation pathway.
Main Results:
- SNX17 expression was downregulated in cardiomyocytes following DOX treatment.
- SNX17 deficiency exacerbated DOX-induced cardiotoxicity, manifesting as increased myocardial damage, fibrosis, impaired contractility, and mortality.
- SNX17 interacts with LMOD2, and its deficiency promotes aberrant LMOD2 degradation via the lysosomal pathway, worsening cardiac systolic dysfunction.
Conclusions:
- SNX17 plays a crucial protective role against doxorubicin-induced cardiotoxicity.
- Targeting SNX17 offers a potential therapeutic strategy for preventing and treating anthracycline-induced cardiotoxicity.
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