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

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Doxorubicin is a potent chemotherapy agent with known cardiotoxic side effects.
• The precise molecular pathways driving doxorubicin-induced cardiomyopathy are not fully understood.
• Ferroptosis, a regulated form of cell death, is implicated in doxorubicin cardiotoxicity.

Purpose of the Study:

• To investigate the role of sorting nexin 3 (SNX3) in doxorubicin-induced cardiomyopathy.
• To determine if SNX3 ablation protects against doxorubicin-induced myocardial injury via ferroptosis modulation.
• To elucidate the molecular mechanisms linking SNX3, ferroptosis, and doxorubicin cardiotoxicity.

Main Methods:

• Generation of cardiomyocyte-specific SNX3 knockout mice.
• Administration of doxorubicin to wild-type and SNX3-deficient mice.
• Assessment of cardiac function, injury biomarkers, inflammation, and oxidative stress.
• Molecular analysis of ferroptosis markers (GPX4), endoplasmic reticulum (ER) stress, and mitochondrial function.
• In vitro studies using erastin (ferroptosis inducer) in SNX3-depleted cardiomyocytes.

Main Results:

• SNX3 deletion normalized cardiac contractile and relaxation function post-doxorubicin exposure.
• SNX3 deficiency reduced cardiac injury biomarkers, inflammation, and oxidative stress.
• Doxorubicin treatment activated GPX4-dependent ferroptosis, which was prevented by SNX3 loss.
• SNX3 deficiency alleviated doxorubicin-induced cell death, ER stress, and mitochondrial dysfunction.
• Erastin exacerbated doxorubicin's detrimental effects in SNX3-depleted cardiomyocytes.

Conclusions:

• SNX3 plays a critical role in mediating doxorubicin-induced cardiotoxicity.
• SNX3 deficiency confers protection against doxorubicin-induced myocardial dysfunction.
• Modulation of GPX4-associated ferroptosis by SNX3 is a key mechanism underlying doxorubicin cardiotoxicity.