Targeting OGF/OGFR signal to mitigate doxorubicin-induced cardiotoxicity

• Published in: Free radical biology & medicine Vol. 223; pp. 398 - 412
• Main Authors: Chen, Xiru, Jian, Dongdong, Xing, Junyue, Cheng, Xiaolei, Wang, Chuan, Wang, Chenqiu, Pan, Jiangpeng, Qi, Xinkun, Wang, Shixing, Li, Zhen, Liu, Ying, Jian, Liguo, Tang, Hao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2024
• Subjects: Animals; Apoptosis - drug effects; Cardiomyocyte apoptosis and ferroptosis; Cardiotoxicity - etiology; Cardiotoxicity - genetics; Cardiotoxicity - metabolism; Cardiotoxicity - pathology; Cardiotoxicity - prevention & control; Doxorubicin - adverse effects; Doxorubicin-induced cardiotoxicity; Enkephalin, Methionine - metabolism; Enkephalin, Methionine - pharmacology; Ferritin gene; Humans; Lipid nanoparticle; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nanoparticles; OGF/OGFR; Receptors, Opioid - genetics; Receptors, Opioid - metabolism; Signal Transduction - drug effects; STAT1; OGF/OGFR; Ferritin gene; Doxorubicin-induced cardiotoxicity; STAT1; Lipid nanoparticle; Cardiomyocyte apoptosis and ferroptosis
• ISSN: 0891-5849; 1873-4596; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2024.08.005

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. [Display omitted] •Circulating OGF has diagnostic potential for predicting anthracycline-associated cardiotoxicity.•OGF/OGFR signaling aggravates Dox-induced cardiomyocyte apoptosis and ferroptosis simultaneously.•OGFR represses the transcription of ferritin genes by dissociating STAT1 from their promoters.•Interference with cardiac OGF/OGFR signaling offers a novel approach for safeguarding against Dox-induced cardiotoxicity.