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

The complete molecular mechanism underlying doxorubicin-induced cardiomyopathy remains incompletely elucidated. In this investigation, we engineered mice with cardiomyocyte-specific knockout ( ) to probe the potential protective effects of ablation on doxorubicin-triggered myocardial injury, focusing on GPX4-dependent ferroptosis. Our findings indicate that deletion normalized heart contractile/relaxation function and thwarted the escalation of cardiac injury biomarkers following doxorubicin exposure. Additionally, 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 -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.