Shao Jingrong, Xiao Rui, Wang Ting, Wang Fengshuo, Wang Bei, Zhang Dongli, Wang Lulu, Li Jingchao, Liu Jiao, Zuo Shengkai
Department of Biopharmaceutics, Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Pharmacy, Tianjin Medical University, Tianjin, China.
College of Biological Science and Medical Engineering, Donghua University, Shanghai, China.
Sci Adv. 2025 Jul 11;11(28):eadw1720. doi: 10.1126/sciadv.adw1720.
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.
阿霉素（DOX）是一种有效的抗癌药物，但其临床应用主要受心脏毒性的限制，这种毒性会导致心肌细胞发生铁死亡和凋亡。虽然阿霉素诱导的心脏毒性（DIC）涉及表观遗传变化，但尚未有系统性的表观遗传干预研究报道。在此，我们通过表观遗传学化合物库筛选，确定BRD4770为一种潜在的抗DIC小分子。BRD4770通过减少活性氧（ROS）生成和脂质过氧化以及维持谷胱甘肽稳态，抑制阿霉素诱导的心肌细胞铁死亡和凋亡。BRD4770治疗可减轻DIC，且不影响阿霉素的抗肿瘤效果。从机制上讲，BRD4770通过减少组蛋白3赖氨酸9位点的甲基化，促进核因子红细胞2相关因子2（Nrf2）/激活转录因子4（ATF4）-溶质载体家族7成员11（SLC7A11）信号通路，并抑制阿霉素诱导的心肌细胞死亡。最后，我们构建了一种负载BRD4770并与心脏靶向肽偶联的ROS响应纳米脂质体用于原代心肌细胞，其对DIC提供了更好的保护作用。这些发现表明，BRD4770有预防心肌细胞死亡相关心肌病的潜力。
