Yang Mengxue, Wang Ting, Shao Jingrong, Ran Xinna, Xiao Rui, Zhao Rui, Wu Chunyan, Ji Ming, Tian Weiping, Sun Huabing, 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.
Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.
Cell Death Dis. 2025 Jul 23;16(1):548. doi: 10.1038/s41419-025-07880-x.
Myocardial infarction (MI) remains one of the leading causes of mortality worldwide, and cardiomyocyte death plays a critical role in cardiac remodeling after MI. Ferroptosis is a recently identified form of iron-dependent programmed cell death that has been shown to be involved in the progression of various cardiovascular diseases, including MI. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a key regulator of cell survival. In this study, we screened an epigenetic target library containing 773 small-molecule compounds and found that (+)-JQ-1(hereafter abbreviated as JQ-1), a BRD4-specific inhibitor, markedly attenuated ferroptosis induced by erastin (a ferroptosis inducer) in cardiomyocytes. Both prophylactic and therapeutic JQ-1 administration significantly improved cardiac remodeling and reduced cardiomyocyte ferroptosis in mice with MI. Mechanistically, JQ-1 protected cardiomyocytes from erastin-induced ferroptosis by downregulating the expression of nicotinate phosphoribosyltransferase (NAPRT) and upregulating the expression of nicotinamide phosphoribosyltransferase (NAMPT) and sirtuin1 (SIRT1). Inhibition of NAMPT or SIRT1 abrogated the protection conferred by JQ-1 in erastin-treated H9C2 cardiomyocytes. The combination of proteolysis-targeting chimeras (PROTACs) with JQ-1 (JQ-1-PROTAC) promoted BRD4 protein degradation and rescued erastin-induced ferroptosis in H9C2 cardiomyocytes, and prevented erastin-induced ferroptosis in human cardiomyocytes. Thus, JQ-1 can protect cardiomyocytes from ferroptosis through the NAMPT-SIRT1 pathway, and JQ-1-based therapy may serve as a novel promising strategy to improve cardiac remodeling after MI.
心肌梗死（MI）仍然是全球主要的死亡原因之一，心肌细胞死亡在MI后的心脏重塑中起关键作用。铁死亡是一种最近被发现的铁依赖性程序性细胞死亡形式，已被证明参与包括MI在内的各种心血管疾病的进展。含溴结构域蛋白4（BRD4）是一种表观遗传阅读器，也是细胞存活的关键调节因子。在本研究中，我们筛选了一个包含773种小分子化合物的表观遗传靶点文库，发现BRD4特异性抑制剂（+）-JQ-1（以下简称JQ-1）显著减轻了心肌细胞中由erastin（一种铁死亡诱导剂）诱导的铁死亡。预防性和治疗性给予JQ-1均能显著改善MI小鼠的心脏重塑并减少心肌细胞铁死亡。机制上，JQ-1通过下调烟酸磷酸核糖基转移酶（NAPRT）的表达以及上调烟酰胺磷酸核糖基转移酶（NAMPT）和沉默调节蛋白1（SIRT1）的表达，保护心肌细胞免受erastin诱导的铁死亡。抑制NAMPT或SIRT1可消除JQ-1对erastin处理的H9C2心肌细胞的保护作用。蛋白水解靶向嵌合体（PROTACs）与JQ-1的组合（JQ-1-PROTAC）促进了BRD4蛋白降解，并挽救了H9C2心肌细胞中erastin诱导的铁死亡，且预防了人心肌细胞中erastin诱导的铁死亡。因此，JQ-1可通过NAMPT-SIRT1途径保护心肌细胞免受铁死亡，基于JQ-1的治疗可能是改善MI后心脏重塑的一种新的有前景的策略。
