SNX3 Promotes Doxorubicin-Induced Cardiomyopathy by Regulating GPX4-Mediated Ferroptosis

Huang, Shuai1; Zou, Fan1; Zhou, Hao2; He, Jinyuan1

2024

10.7150/ijms.95466

INTERNATIONAL JOURNAL OF MEDICAL SCIENCES   影响因子和分区

1449-1907

The complete molecular mechanism underlying doxorubicin-induced cardiomyopathy remains incompletely elucidated. In this investigation, we engineered mice with cardiomyocyte-specific sorting nexin 3 knockout (SNX3Cko) to probe the potential protective effects of SNX3 ablation on doxorubicin-triggered myocardial injury, focusing on GPX4-dependent ferroptosis. Our findings indicate that SNX3 deletion normalized heart contractile/relaxation function and thwarted the escalation of cardiac injury biomarkers following doxorubicin exposure. Additionally, SNX3 deletion in the heart mitigated the inflammatory response and oxidative stress in the presence of doxorubicin. At the molecular level, the detrimental effects of doxorubicin-induced cell death, endoplasmic reticulum (ER) stress, and mitochondrial dysfunction were alleviated by SNX3 deficiency. Molecular analysis revealed the activation of GPX4-mediated ferroptosis by doxorubicin, whereas loss of SNX3 prevented the initiation of GPX4-dependent ferroptosis. Furthermore, treatment with erastin, a ferroptosis inducer, markedly reduced cell viability, exacerbated ER stress, and induced mitochondrial dysfunction in SNX3-depleted cardiomyocytes upon doxorubicin exposure. In summary, our results demonstrate that SNX3 deficiency shielded the heart from doxorubicin-induced myocardial dysfunction by modulating GPX4-associated ferroptosis.

SNX3 doxorubicin GPX4 ferroptosis

SCI

英语

其他

General & Internal Medicine

Medicine, General & Internal

WOS:001287431000005

IVYSPRING INT PUBL

Web of Science

1.Sun Yat Sen Univ, Affiliated Hosp 3, Dept Cardiothorac Surg, Guangzhou 510630, Peoples R China
2.Southern Univ Sci & Technol, Sch Med, Shenzhen, Guangdong, Peoples R China

Huang, Shuai,Zou, Fan,Zhou, Hao,et al. SNX3 Promotes Doxorubicin-Induced Cardiomyopathy by Regulating GPX4-Mediated Ferroptosis[J]. INTERNATIONAL JOURNAL OF MEDICAL SCIENCES,2024,21(9).

Huang, Shuai,Zou, Fan,Zhou, Hao,&He, Jinyuan.(2024).SNX3 Promotes Doxorubicin-Induced Cardiomyopathy by Regulating GPX4-Mediated Ferroptosis.INTERNATIONAL JOURNAL OF MEDICAL SCIENCES,21(9).

Huang, Shuai,et al."SNX3 Promotes Doxorubicin-Induced Cardiomyopathy by Regulating GPX4-Mediated Ferroptosis".INTERNATIONAL JOURNAL OF MEDICAL SCIENCES 21.9(2024).