BRD4770 protects against DOX-induced cardiotoxicity by inhibiting apoptosis and ferroptosis.

Doxorubicin (DOX) is an effective anticancer drug, but its clinical utility is limited mainly by cardiotoxicity causing cardiomyocyte ferroptosis and apoptosis. While DOX-induced cardiotoxicity (DIC) involves epigenetic changes, no systematic epigenetic intervention studies have been reported. Here, we identified BRD4770 as a potential small molecule against DIC through the Epigenetics Compound Library screening. BRD4770 inhibited DOX-induced cardiomyocyte ferroptosis and apoptosis by reducing reactive oxygen species (ROS) production and lipid peroxidation and maintaining glutathione homeostasis. BRD4770 treatment alleviated DIC without affecting the antitumor effects of DOX. Mechanistically, BRD4770 promoted nuclear factor erythroid 2-related factor 2 (Nrf2)/activating transcription factor 4 (ATF4)-solute carrier family 7 member 11 (SLC7A11) signaling and suppressed DOX-induced cardiomyocyte death by reducing methylation of lysine 9 on histone 3. Last, we constructed a ROS-responsive nanoliposome loaded with BRD4770 and conjugated with the cardiac-targeting peptide for primary cardiomyocyte, which provided better protection against DIC. These findings suggest that BRD4770 has the potential to prevent cardiomyocyte death-related cardiomyopathy.