Abstract：
Enkephalins are reportedly correlated with heart function. However, their regulation in the heart remains unexplored. This study revealed a substantial increase in circulating levels of opioid growth factor (OGF) (also known as methionine enkephalin) and myocardial expression levels of both OGF and its receptor (OGFR) in subjects treated with doxorubicin (Dox). Silencing OGFR through gene knockout or using adeno-associated virus serotype 9 carrying small hairpin RNA effectively alleviated Dox-induced cardiotoxicity (DIC) in mice. Conversely, OGF supplementation exacerbated DIC manifestations, which could be abolished by administration of the OGFR antagonist naltrexone (NTX). Mechanistically, the previously characterized OGF/OGFR/P21 axis was identified to facilitate DIC-related cardiomyocyte apoptosis. Additionally, OGFR was observed to dissociate STAT1 from the promoters of ferritin genes (FTH and FTL), thereby repressing their transcription and exacerbating DIC-related cardiomyocyte ferroptosis. To circumvent the compromised therapeutic effects of Dox on tumors owing to OGFR blockade, SiO2-based modifiable lipid nanoparticles were developed for heart-targeted delivery of NTX. The pretreatment of tumor-bearing mice with the assembled NTX nanodrug successfully provided cardioprotection against Dox toxicity without affecting Dox therapy in tumors. Taken together, this study provides a novel understanding of Dox cardiotoxicity and sheds light on the development of cardioprotectants for patients with tumors receiving Dox treatment.
摘要：
据报道脑啡肽与心脏功能相关。然而,它们在心脏中的调节仍未被探索。这项研究表明，在接受多柔比星（Dox）治疗的受试者中，阿片样物质生长因子（OGF）（也称为甲硫氨酸脑啡肽）的循环水平以及OGF及其受体（OGFR）的心肌表达水平显着增加。通过基因敲除或使用携带小发夹RNA的腺相关病毒血清型9沉默OGFR有效地减轻了小鼠中Dox诱导的心脏毒性(DIC)。相反，补充OGF会加剧DIC表现，可以通过施用OGFR拮抗剂纳曲酮（NTX）来消除。机械上,先前表征的OGF/OGFR/P21轴被鉴定为促进DIC相关心肌细胞凋亡.此外,观察到OGFR将STAT1与铁蛋白基因（FTH和FTL）的启动子解离，从而抑制其转录并加剧DIC相关的心肌细胞铁性凋亡。为了避免由于OGFR阻断而导致的Dox对肿瘤的治疗效果受损，基于SiO2的可修饰脂质纳米颗粒被开发用于NTX的心脏靶向递送。用组装的NTX纳米药物预处理荷瘤小鼠成功地提供了针对Dox毒性的心脏保护,而不影响肿瘤中的Dox治疗。一起来看,这项研究提供了对Dox心脏毒性的新认识，并为接受Dox治疗的肿瘤患者的心脏保护剂的开发提供了启示。
