Abstract 1680P
Background
Doxorubicin is an effective and essential component of many cancer regimens. However, its clinical use is hampered by lethal cardiomyopathy. This study sought to investigate the potential cardioprotective role of the GPX4 activator in doxorubicin-induced cardiotoxicity.
Methods
Survival time was measured following 20mg/kg of doxorubicin in C57BL/6 mice with various inhibitors of ferroptosis and GPX4 activator. Single-cell sequence, lipidomic analyses, and GPX4 heterodeletion mice were performed to explore the molecular mechanism by which the GPX4 activator alleviates doxorubicin-induced cardiotoxicity. The dual cardioprotective and antitumor action of the GPX4 activator was also assessed in mouse mammary tumor models. Six patients receiving four cycles of doxorubicin-based chemotherapy enrolled in this study. Three patients received GPX4 activator (selenium-enriched mushroom tablets, 300μg selenium daily) for seven days before each chemotherapy cycle, the other patients received a placebo. Serum cardiac troponin I (cTnI) was measured at diagnosis (before doxorubicin-based chemotherapy), the second and third day after administration of doxorubicin-based chemotherapy.
Results
Integrated with single-cell sequence and lipidomic analyses, we found that ferroptosis, biosynthesis of unsaturated fatty acids, arachidonic acid metabolism, and glutathione metabolism played a pivotal role in the doxorubicin-induced cardiomyopathy. GPX4 activator significantly reduced arachidonic acid levels and doxorubicin-induced mortality compared to dexrazoxane, ferrostatin-1, and saline (60% vs 30% vs 30% vs 0%, p<0.05). Genetic depletion of GPX4 abolished the protective function of GPX4 activator against doxorubicin-induced cardiotoxicity in C57BL/6 mice. GPX4 activator did not compromise the reduction of cancer burden by doxorubicin in multiple cancer models while providing cardiac protection in the same animals. GPX4 activator significantly decreased the elevations of cardiac cTnI induced by doxorubicin-based chemotherapy.
Conclusions
GPX4 activator prevents cardiac injury by suppressing ferroptosis induced by doxorubicin. Activating GPX4 is a promising therapeutic strategy to protect against doxorubicin-induced cardiomyopathy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
This study was supported by the National Natural Science Foundation of China (81660503, 82160490).
Disclosure
All authors have declared no conflicts of interest.