2. Academic Validation
  3. A BACH1 inhibitor ameliorates myocardial infarction and limb ischemia in mice

A BACH1 inhibitor ameliorates myocardial infarction and limb ischemia in mice

  • Mol Ther. 2025 Jul 16:S1525-0016(25)00544-1. doi: 10.1016/j.ymthe.2025.07.008.
Jiayi Lin 1,  Xin Liu 2,  Qinhan Li 1,  Fei Ge 1,  Jinghua Ma 1,  Xianlong Ng 1,  Qi Pan 1,  Xiangxiang Wei 1,  Qingjun Jiang 1,  Jiayu Jin 1,  Siyu Ma 1,  Yunquan He 1,  Yongbo Li 1,  Nan Jiang 1,  Yannan Hou 1,  Yueyang Yu 1,  Xiaoke Lin 1,  Quanshan Jin 1,  Chengguo Xu 1,  Xinhong Wang 1,  Xiuling Zhi 1,  Qianqian Liang 1,  Lindi Jiang 1,  Elena Osto 3,  Jieyu Guo 4,  Xiu-Jie Wang 5,  Dan Meng 6
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 2 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
  • 3 The Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology, and Inflammation, Medical University of Graz, Styria, Austria.
  • 4 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: guojieyu@fudan.edu.cn.
  • 5 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: xjwang@genetics.ac.cn.
  • 6 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address: dmeng@fudan.edu.cn.
PMID: 40676837 DOI: 10.1016/j.ymthe.2025.07.008
Abstract

The transcription factor BTB and CNC homology 1 (BACH1) is linked to coronary artery disease risk and impairs angiogenesis after ischemic injury. However, there is a scarcity of specific BACH1 inhibitors. This study identifies BI033 as a selective BACH1 inhibitor, confirming its binding to the 91st alanine in BACH1's N-terminal. BI033 shows lower toxicity in human umbilical vein endothelial cells (HUVECs) than the BACH1 inhibitor HPPE. Intraperitoneal BI033 injections in mice enhance vascular density in the infarct border zone, reduce scar size, and ameliorate contractile dysfunction post-myocardial infarction (MI). Intramuscular injections of BI033 in the ischemic hindlimbs of mice also enhance perfusion and vascular density in the ischemic tissue. Mechanistically, BI033 decreases BACH1's nuclear localization and the enrichment of its target genes like heme oxygenase-1 and vascular endothelial growth factor A, while enhancing nuclear factor erythroid 2-related factor 2's nuclear accumulation and its enrichment of target genes in HUVECs. Additionally, BI033 reduces BACH1-histone deacetylase 1 interaction, elevating the enrichment of the histone 3 lysine 27 acetylation at BACH1 target genes, leading to increased expression of angiogenic-related genes. Thus, the BACH1 inhibitor BI033 could serve as therapy for MI and peripheral ischemic vascular disease.

Keywords

BACH1 inhibitor; BI033; angiogenesis; ischemia; myocardial infarction.

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