2. Academic Validation
  3. Berberine as a novel ACSL4 inhibitor to suppress endothelial ferroptosis and atherosclerosis

Berberine as a novel ACSL4 inhibitor to suppress endothelial ferroptosis and atherosclerosis

  • Biomed Pharmacother. 2024 Aug:177:117081. doi: 10.1016/j.biopha.2024.117081.
Yang Hong 1,  Jing Feng 1,  Zijia Dou 1,  Xiuxiu Sun 1,  Yingying Hu 1,  Zhouxiu Chen 1,  Ling Liu 1,  Henghui Xu 1,  Menghan Du 1,  Pingping Tang 1,  Xin Liu 2,  Yong Zhang 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin, China; State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, China.
  • 2 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin, China; State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, China. Electronic address: freyaliuxin@163.com.
  • 3 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, the Second Affiliated Hospital, Harbin Medical University, Harbin, China; State Key Labratoray -Province Key Laboratories of Biomedicine-Pharmaceutics of China, and Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin, China; Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, China. Electronic address: hmuzhangyong@hotmail.com.
PMID: 38971008 DOI: 10.1016/j.biopha.2024.117081
Abstract

The discovery of an inhibitor for acyl-CoA synthetase long-chain family member 4 (ACSL4), a protein involved in the process of cell injury through Ferroptosis, has the potential to ameliorate cell damage. In this study, we aimed to investigate the potential of berberine (BBR) as an inhibitor of ACSL4 in order to suppress endothelial Ferroptosis and provide protection against atherosclerosis. An atherosclerosis model was created in apoE-/- mice by feeding a high fat diet for 16 weeks. Additionally, a mouse model with endothelium-specific overexpression of ACSL4 was established. BBR was administered orally to assess its potential therapeutic effects on atherosclerosis. Human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low density lipoprotein (ox-LDL) to simulate atherosclerotic endothelial damage in vitro. The interaction between ACSL4 and BBR has been confirmed, with BBR playing a role in inhibiting erastin-induced Ferroptosis by regulating ACSL4. Additionally, BBR has been found to inhibit lipid deposition, plaque formation, and collagen deposition in the aorta, thereby delaying the progression of atherosclerosis. It also restored the abnormal expression of ferroptosis-related proteins in atherosclerotic vascular endothelial cells both in vivo and in vitro. In conclusion, BBR, acting as an ACSL4 inhibitor, can improve atherosclerosis by inhibiting Ferroptosis in endothelial cells. This highlights the potential of targeted inhibition of vascular endothelial ACSL4 as a strategy for treating atherosclerosis, with BBR being a candidate for this purpose.

Keywords

ACSL4; Atherosclerosis; Berberine; Endothelial; Ferroptosis.

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