2. Academic Validation
  3. A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY

A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY

  • Theranostics. 2025 Mar 18;15(10):4325-4344. doi: 10.7150/thno.105782.
Zhidan Zhang 1,  Meijie Chen 1,  Yitong Xu 2,  Zhihua Wang 1,  Zhenghong Liu 1,  Chenyang He 1,  Fanshun Zhang 1,  Xiaojun Feng 1,  Xiayun Ni 1,  Yuanli Chen 3,  Jixia Wang 4,  Xinmiao Liang 4,  Zhifu Xie 5,  Jingya Li 5,  Maciej Banach 6,  Jaroslav Pelisek 7,  Yuqing Huo 8,  Yunhui Hu 9,  Paul C Evans 10,  Li Wang 11,  Xiao-Yu Tian 12,  Jianbo Xiao 13,  Yuhua Shang 14,  Yijun Zheng 15,  Xunde Xian 2,  Jianping Weng 1 16 17,  Suowen Xu 1 16 17
Affiliations

Affiliations

  • 1 Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
  • 2 Institute of Cardiovascular Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 3 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
  • 4 Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
  • 5 State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences. Shanghai, 201203, China.
  • 6 Department of Preventive Cardiology and Lipidology, Medical University of Lodz 23 (MUL), Rzgowska 281/289, 93-338, Lodz, Poland.
  • 7 Department of Vascular Surgery, University Hospital Zurich, Zurich, Switzerland.
  • 8 Department of Ophthalmology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 9 Tasly Pharmaceutical Group Co., Ltd., Tianjin, 300410, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin, 301617, China.
  • 10 Centre for Biochemical Pharmacology, William Harvey Research Institute, Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ, UK.
  • 11 Department of Biomedical Sciences, City University of Hong Kong, China.
  • 12 School of Biomedical Sciences, Chinese University of Hong Kong, NT, Hong Kong SAR, China.
  • 13 Universidade de Vigo, Department of Analytical and Food Chemistry, Faculty of Sciences, Ourense, 32004, Spain.
  • 14 Anhui Genebiol Biotech. Ltd., Hefei, 230000, China.
  • 15 Clinical Pharmacy (Sino-Foreign Cooperation) Class, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
  • 16 Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei, 230001, China.
  • 17 Institute of Endocrine and Metabolic Diseases, University of Science and Technology of China, Hefei, 230001, China.
PMID: 40225566 DOI: 10.7150/thno.105782
Abstract

Rationale: Atherosclerotic Cardiovascular Disease (ASCVD) represents the predominant cause of mortality and morbidity globally. Given the established role of hypercholesterolemia as a significant risk factor for ASCVD, the discovery of new lipid-lowering medications is of paramount importance. ATP Citrate Lyase (ACLY) is a crucial enzyme in cellular metabolism, providing acetyl-CoA as the building block for the biosynthesis of fatty acids and Cholesterol. Consequently, it has emerged as a promising drug target for innovative treatments of lipid metabolic disorders. Methods: Virtual screening of a natural product library was performed to identify small-molecule ACLY inhibitors, leading to the discovery of isoginkgetin (ISOGK). The lipid-lowering and anti-atherosclerotic effects of ISOGK were validated in hypercholesterolemic diet-induced animal models (mice and hamsters). The inhibitory effects of ISOGK on ACLY enzymatic activity were measured using commercial assay kits. The direct interaction between ISOGK and ACLY was confirmed by surface plasmon resonance (SPR) and cellular thermal shift assays (CETSA). Liver-specific ACLY knockdown mice were generated using GalNAc-conjugated siRNA (GalNAc-siAcly). Results: ISOGK directly bind to ACLY and inhibit its enzymatic activity in vitro and in vivo. By inhibiting ACLY, ISOGK treatment thus alleviates hypercholesterolemia and atherosclerosis in mice and hamsters. However, ISOGK fails to attenuate lipid accumulation and the expression of lipid-metabolism related genes in Acly knockout or depleted hepatocytes. In vivo, the lipid-lowering and anti-atherosclerotic effects of ISOGK were reversed by hepatic knockdown of Acly via treatment with GalNAc-siAcly in mice. Conclusions: Taken together, the present study identifies ISOGK as an effective and naturally-occurring small-molecule inhibitor of ACLY that limits hypercholesterolemia and atherosclerosis. ISOGK thus serves as a promising drug lead in cardiovascular therapeutics.

Keywords

ATP-Citrate lyase (ACLY); Atherosclerosis; Hyperlipidemia; Isoginkgetin; lipid metabolism.

Figures
Products