THBru ameliorates atherosclerosis by inhibiting endothelial ferroptosis via regulation of the super-enhancer-associated ABCC1

  • Acta Pharm Sin B. 2025 Dec;15(12):6461-6477. doi: 10.1016/j.apsb.2025.09.035.
Jing Feng  1  2  3 ,  Yingying Hu  4 ,  Xiuxiu Sun  1  2  3 ,  Yutong Hao  1  2  3 ,  Yiyang Li  1  2  3 ,  Qiang Huang  1  2  3 ,  Yanli Xie  1  2  3 ,  Jin Gao  1  2  3 ,  Ange Hu  1  2  3 ,  Yang Hong  1  2  3 ,  Xu Wang  1  2  3 ,  Heng Liu  1  2  3 ,  Zijia Dou  1  2  3 ,  Lina Yao  1  2  3 ,  Qi Lu  1  2  3 ,  Jennifer Wang  5 ,  Philipp Kopylov  6 ,  Weina Han  7 ,  Yong Zhang  1  2  3 ,  Xin Liu  1  2  3
Affiliations
  • 1. State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Pharmacy, Department of Cardiology, The Second Affiliated Hospital, Harbin Medical University, Harbin 150081, China.
  • 2. Department of Pharmacology, (SKLFZCD, State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China.
  • 3. Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin 150081, China.
  • 4. Department of Pharmacy, The First Hospital of China Medical University, Shenyang 110001, China.
  • 5. Department of Medicine, Faculty of Medicine, Université de Laval, Québec G1V 0A6, Canada.
  • 6. Department of Preventive and Emergency Cardiology, Sechenov First Moscow State Medical University, Moscow 119991, Russian Federation.
  • 7. Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
PMID: 41477343 DOI: 10.1016/j.apsb.2025.09.035
Abstract

Atherosclerosis is a chronic vascular disease closely associated with endothelial dysfunction. Ferroptosis, a major factor in endothelial dysfunction, plays a pivotal role in the progression of atherosclerosis. The development of drugs targeting endothelial Ferroptosis offers a potential therapeutic approach for atherosclerosis. This study aimed to assess the potential impact of tetrahydroberberrubine (THBru) on atherosclerosis and unravel its molecular mechanism underlying endothelial protection. Our results demonstrated that THBru significantly reduced plaque formation in the aortas of atherosclerotic mice. Through transcriptome Sequencing and further verification, we observed that THBru mitigated endothelial Ferroptosis in atherosclerosis by enhancing glutathione homeostasis and decreasing Reactive Oxygen Species (ROS) accumulation. Mechanistically, bioinformatic analysis demonstrated that THBru reduced the expression of the super-enhancer (SE) regulatory gene ATP-binding cassette subfamily C member 1 (ABCC1). The transcription factor BTB and CNC homology 1 (BACH1) was responsible for ABCC1 transcription by binding to its SE (ABCC1-SE), whereas THBru effectively inhibited the activity of ABCC1-SE. Furthermore, THBru promoted adenosine monophosphate-activated protein kinase (AMPK) activation, thereby negatively regulating BACH1 and the downstream ABCC1/Ferroptosis signaling pathway. Collectively, these findings highlight THBru as a promising candidate for treating atherosclerosis, featuring a novel mechanism that inhibits endothelial Ferroptosis through the AMPK/BACH1 axis to regulate ABCC1-SE.

Keywords
ABCC1; AMPK; Atherosclerosis; BACH1; Endothelial; Ferroptosis; Super-enhancer; Tetrahydroberberrubine.
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