2. Academic Validation
  3. (+)-JQ-1 alleviates cardiac injury in myocardial infarction by inhibiting ferroptosis through the NAMPT/SIRT1 pathway

(+)-JQ-1 alleviates cardiac injury in myocardial infarction by inhibiting ferroptosis through the NAMPT/SIRT1 pathway

  • Cell Death Dis. 2025 Jul 23;16(1):548. doi: 10.1038/s41419-025-07880-x.
Mengxue Yang # 1,  Ting Wang # 1,  Jingrong Shao # 1,  Xinna Ran 1,  Rui Xiao 1,  Rui Zhao 2,  Chunyan Wu 1,  Ming Ji 3,  Weiping Tian 2,  Huabing Sun 3,  Jiao Liu 4,  Shengkai Zuo 5
Affiliations

Affiliations

  • 1 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.
  • 2 Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, China.
  • 3 Department of Chemical Biology, School of Pharmacy, Tianjin Medical University, Tianjin, China.
  • 4 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. drliujiao@tmu.edu.cn.
  • 5 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. zuoshengkai@tmu.edu.cn.
  • # Contributed equally.
PMID: 40695797 DOI: 10.1038/s41419-025-07880-x
Abstract

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.

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