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Updated: Jan 9, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
The FAK-NRF2 Axis Alleviates DOX-Induced Cardiotoxicity by Inhibiting Ferroptosis
Ying Zhao1,2, Mo Chen1, Linghui Kong1
1Department of Anesthesiology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.
Abstract:
Doxorubicin (DOX), a prevalent anthracycline chemotherapeutic agent, is associated with considerable cardiotoxicity, the molecular mechanisms of which remain incompletely understood. Focal adhesion kinase (FAK), a non-receptor protein tyrosine kinase, plays a crucial role in cardiac survival signaling during both developmental and pathological stress conditions. In this study, we demonstrate that FAK overexpression in SKOV3 mice and AC16 cardiomyocytes ameliorates DOX-induced cardiomyopathy by inhibiting ferroptosis. Mechanistically, DOX treatment induces ferroptosis in cardiomyocytes by suppressing FAK activity. Furthermore, we reveal that FAK overexpression reduces DOX cardiotoxicity, at least in part, through the upregulation of the transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2). The protective effects of FAK against myocardial injury are nullified by NRF2 knockdown. Additionally, histone deacetylase 5 (HDAC5) may be involved in this protective pathway. These findings identify FAK as a critical regulator of DOX-induced cardiotoxicity and suggest that enhancing the FAK/NRF2/HDAC5 signaling axis in cardiac tissue could represent a promising strategy for preserving myocardial function in patients.
Insights
Focal adhesion kinase (FAK) protects against doxorubicin (DOX) cardiotoxicity by inhibiting ferroptosis. Enhancing the FAK/NRF2 pathway may preserve heart function in patients undergoing chemotherapy.
Area of Science:
- Cardiology
- Molecular Biology
- Oncology
Background:
- Doxorubicin (DOX) chemotherapy causes significant cardiotoxicity.
- The molecular mechanisms underlying DOX-induced cardiotoxicity are not fully understood.
- Focal adhesion kinase (FAK) is vital for cardiac survival signaling.
Purpose of the Study:
- To investigate the role of FAK in DOX-induced cardiotoxicity.
- To elucidate the molecular mechanisms by which FAK influences DOX cardiotoxicity.
- To explore potential therapeutic strategies targeting the FAK pathway.
Main Methods:
- Overexpression of FAK in SKOV3 mice and AC16 cardiomyocytes.
- Assessment of DOX-induced cardiotoxicity and ferroptosis.
- Analysis of the FAK/NRF2/HDAC5 signaling axis.
- NRF2 knockdown experiments.
Main Results:
- FAK overexpression ameliorated DOX-induced cardiomyopathy by inhibiting ferroptosis.
- DOX treatment suppressed FAK activity, leading to ferroptosis in cardiomyocytes.
- FAK overexpression upregulated Nuclear factor erythroid 2-related factor 2 (NRF2), conferring protection.
- NRF2 knockdown abolished the protective effects of FAK.
- Histone deacetylase 5 (HDAC5) was implicated in the protective pathway.
Conclusions:
- FAK is a critical regulator of DOX-induced cardiotoxicity.
- FAK protects cardiac cells from DOX-induced ferroptosis, partly via NRF2.
- Enhancing the FAK/NRF2/HDAC5 signaling axis is a potential therapeutic strategy for DOX cardiotoxicity.
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