A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY
文献类型：期刊论文
| 作者 | Zhang, Zhidan18; Chen, Meijie18; Xu, Yitong1; Wang, Zhihua18; Liu, Zhenghong18; He, Chenyang18; Zhang, Fanshun18; Feng, Xiaojun18; Ni, Xiayun18; Chen, Yuanli2 |
| 刊名 | THERANOSTICS
 |
| 出版日期 | 2025 |
| 卷号 | 15期号:10页码:4325-4344 |
| 关键词 | Atherosclerosis Hyperlipidemia ATP-Citrate lyase (ACLY) lipid metabolism Isoginkgetin |
| ISSN号 | 1838-7640 |
| DOI | 10.7150/thno.105782 |
| 英文摘要 | 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. |
| WOS关键词 | GINKGO-BILOBA EXTRACT ; CORONARY-ARTERY-DISEASE ; DE-NOVO LIPOGENESIS ; ATP-CITRATE LYASE ; FAMILIAL HYPERCHOLESTEROLEMIA ; ENDOTHELIAL DYSFUNCTION ; IN-VITRO ; HYPERLIPIDEMIA ; MANAGEMENT ; DEATH |
| 资助项目 | Program for Innovative Research Team of The First Affiliated Hospital of USTC[12411530127] ; Anhui Provincial Natural Science Foundation[CXGG02] ; USTC Research Funds of the Double First-Class Initiative[2208085J08] ; Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM[YD9110002089] ; Humboldt Research Fellowship from Alexander von Humboldt Foundation, Germany |
| WOS研究方向 | Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:001473295700006 |
| 出版者 | IVYSPRING INT PUBL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/317551]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Xian, Xunde; Weng, Jianping; Xu, Suowen |
| 作者单位 | 1.Peking Univ, Inst Cardiovasc Sci, Sch Basic Med Sci, State Key Lab Vasc Homeostasis & Remodeling, Beijing, Peoples R China 2.Hefei Univ Technol, Coll Food & Biol Engn, Key Lab Metab & Regulat Major Dis, Anhui Higher Educ Inst, Hefei, Peoples R China 3.Chinese Acad Sci, Key Lab Separat Sci Analyt Chem, Dalian Inst Chem Phys, Dalian 116023, Peoples R China 4.Univ Sci & Technol China, Inst Endocrine & Metab Dis, Hefei 230001, Peoples R China 5.Anhui Prov Key Lab Metab Hlth & Panvascular Dis, Hefei 230001, Peoples R China 6.Tianjin Univ Tradit Chinese Med, Sch Chinese Mat Med, Clin Pharm Sino Foreign Cooperat Class, Tianjin 301617, Peoples R China 7.Anhui Genebiol Biotech LTD, Hefei 230000, Peoples R China 8.Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Peoples R China 9.Univ Vigo, Fac Sci, Dept Analyt & Food Chem, Orense 32004, Spain 10.City Univ Hong Kong, Dept Biomed Sci, Hong Kong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Zhidan,Chen, Meijie,Xu, Yitong,et al. A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY[J]. THERANOSTICS,2025,15(10):4325-4344. |
| APA | Zhang, Zhidan.,Chen, Meijie.,Xu, Yitong.,Wang, Zhihua.,Liu, Zhenghong.,...&Xu, Suowen.(2025).A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY.THERANOSTICS,15(10),4325-4344. |
| MLA | Zhang, Zhidan,et al."A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY".THERANOSTICS 15.10(2025):4325-4344. |
入库方式： OAI收割
来源：上海药物研究所
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