NEDD4L-Mediated Ubiquitination of GPX4 Exacerbates Doxorubicin-Induced Cardiotoxicity

Ke, Jiaxing; Li, Lingjia; Chen, Shuling; Liao, Chenxin; Peng, Feng; Chai, Dajun; Lin, Jinxiu

doi:10.3390/ijms26178201

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Open AccessArticle

NEDD4L-Mediated Ubiquitination of GPX4 Exacerbates Doxorubicin-Induced Cardiotoxicity

by

Jiaxing Ke

^†,

Lingjia Li

^†

,

Shuling Chen

^*,

Chenxin Liao

,

Feng Peng

,

Dajun Chai

and

Jinxiu Lin

^*

The Higher Educational Key Laboratory for Cardiovascular Disease of Fujian Province, Clinical Research Center for Metabolic Heart Disease of Fujian Province, Cardiovascular Department, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(17), 8201; https://doi.org/10.3390/ijms26178201 (registering DOI)

Submission received: 22 July 2025 / Revised: 15 August 2025 / Accepted: 21 August 2025 / Published: 23 August 2025

(This article belongs to the Section Molecular Toxicology)

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Abstract

Doxorubicin (DOX) is an anthracycline chemotherapeutic agent that is clinically limited by doxorubicin-induced cardiotoxicity (DIC), with ferroptosis and apoptosis identified as key mechanisms. As an antioxidant enzyme, GPX4 undergoes ubiquitin-mediated degradation during myocardial ischemia–reperfusion injury; however, the role of its ubiquitination in DIC remains unclear. This study revealed that GPX4 undergoes ubiquitinated degradation during DIC, exacerbating ferroptosis and apoptosis in cardiomyocytes. NEDD4L was found to interact with GPX4, and its expression was upregulated in DOX-treated mouse myocardial tissues and cardiomyocytes. NEDD4L knockdown alleviated DIC, as well as ferroptosis and apoptosis in cardiomyocytes. Mechanistically, NEDD4L recognizes GPX4 through its WW domain and mediates K48-linked ubiquitination and degradation of GPX4 under DOX stimulation via its HECT domain. Knockdown of NEDD4L reduced DOX-induced GPX4 ubiquitination levels and subsequent degradation. Notably, while NEDD4L knockdown mitigated DOX-induced cell death, concurrent GPX4 knockdown attenuated this protective effect, indicating that GPX4 is a key downstream target of NEDD4L in regulating cardiomyocyte death. These findings identify NEDD4L as a potential therapeutic target for preventing and treating DIC.

Keywords: doxorubicin; cardiotoxicity; NEDD4L; GPX4; ubiquitination

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MDPI and ACS Style

Ke, J.; Li, L.; Chen, S.; Liao, C.; Peng, F.; Chai, D.; Lin, J. NEDD4L-Mediated Ubiquitination of GPX4 Exacerbates Doxorubicin-Induced Cardiotoxicity. Int. J. Mol. Sci. 2025, 26, 8201. https://doi.org/10.3390/ijms26178201

AMA Style

Ke J, Li L, Chen S, Liao C, Peng F, Chai D, Lin J. NEDD4L-Mediated Ubiquitination of GPX4 Exacerbates Doxorubicin-Induced Cardiotoxicity. International Journal of Molecular Sciences. 2025; 26(17):8201. https://doi.org/10.3390/ijms26178201

Chicago/Turabian Style

Ke, Jiaxing, Lingjia Li, Shuling Chen, Chenxin Liao, Feng Peng, Dajun Chai, and Jinxiu Lin. 2025. "NEDD4L-Mediated Ubiquitination of GPX4 Exacerbates Doxorubicin-Induced Cardiotoxicity" International Journal of Molecular Sciences 26, no. 17: 8201. https://doi.org/10.3390/ijms26178201

APA Style

Ke, J., Li, L., Chen, S., Liao, C., Peng, F., Chai, D., & Lin, J. (2025). NEDD4L-Mediated Ubiquitination of GPX4 Exacerbates Doxorubicin-Induced Cardiotoxicity. International Journal of Molecular Sciences, 26(17), 8201. https://doi.org/10.3390/ijms26178201

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NEDD4L-Mediated Ubiquitination of GPX4 Exacerbates Doxorubicin-Induced Cardiotoxicity

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