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

Zhidan Zhang; Meijie Chen; Yitong Xu; Zhihua Wang; Zhenghong Liu; Chenyang He; Fanshun Zhang; Xiaojun Feng; Xiayun Ni; Yuanli Chen; Jixia Wang; Xinmiao Liang; Zhifu Xie; Jingya Li; Maciej Banach; Jaroslav Pelisek; Yuqing Huo; Yunhui Hu; Paul C. Evans; Li Wang; Xiao-yu Tian; Jianbo Xiao; Yuhua Shang; Yijun Zheng; Xunde Xian; Jianping Weng; Suowen Xu

doi:10.7150/thno.105782

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

Zhidan Zhang (Co-first Author)
, Meijie Chen (Co-first Author)
, Yitong Xu (Co-first Author)
, Zhihua Wang
, Zhenghong Liu
, Chenyang He
, Fanshun Zhang
, Xiaojun Feng
, Xiayun Ni
, Yuanli Chen
, Jixia Wang
, Xinmiao Liang
, Zhifu Xie
, Jingya Li
, Maciej Banach
, Jaroslav Pelisek
, Yuqing Huo
, Yunhui Hu
, Paul C. Evans
, Li Wang

Xiao-yu Tian, Jianbo Xiao, Yuhua Shang, Yijun Zheng, Xunde Xian^*, Jianping Weng^*, Suowen Xu^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

12 Citations (Scopus)

17 Downloads (CityUHK Scholars)

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.

© The author(s).

Original language	English
Pages (from-to)	4325-4344
Journal	Theranostics
Volume	15
Issue number	10
Online published	18 Mar 2025
DOIs	https://doi.org/10.7150/thno.105782
Publication status	Published - 2025

Funding

This study was supported by National Natural Science Foundation of China (Grant Nos. 82370444, 12411530127). This work was also supported by the Program for Innovative Research Team of The First Affiliated Hospital of USTC (CXGG02), Anhui Provincial Natural Science Foundation (Grant No. 2208085J08), USTC Research Funds of the Double First-Class Initiative (no. YD9110002089) and the Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM. SX is a recipient of Humboldt Research Fellowship from Alexander von Humboldt Foundation, Germany.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

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

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This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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Zhang, Z., Chen, M., Xu, Y., Wang, Z., Liu, Z., He, C., Zhang, F., Feng, X., Ni, X., Chen, Y., Wang, J., Liang, X., Xie, Z., Li, J., Banach, M., Pelisek, J., Huo, Y., Hu, Y., Evans, P. C., ... Xu, S. (2025). A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY. Theranostics, 15(10), 4325-4344. https://doi.org/10.7150/thno.105782

@article{e2f7330d69184414a5c8a88f1bbb0ec1,

title = "A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY",

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. {\textcopyright} The author(s).",

keywords = "Atherosclerosis, ATP-Citrate lyase (ACLY), Hyperlipidemia, Isoginkgetin, lipid metabolism",

author = "Zhidan Zhang and Meijie Chen and Yitong Xu and Zhihua Wang and Zhenghong Liu and Chenyang He and Fanshun Zhang and Xiaojun Feng and Xiayun Ni and Yuanli Chen and Jixia Wang and Xinmiao Liang and Zhifu Xie and Jingya Li and Maciej Banach and Jaroslav Pelisek and Yuqing Huo and Yunhui Hu and Evans, \{Paul C.\} and Li Wang and Xiao-yu Tian and Jianbo Xiao and Yuhua Shang and Yijun Zheng and Xunde Xian and Jianping Weng and Suowen Xu",

year = "2025",

doi = "10.7150/thno.105782",

language = "English",

volume = "15",

pages = "4325--4344",

journal = "Theranostics",

issn = "1838-7640",

publisher = "Ivyspring International Publisher",

number = "10",

}

Zhang, Z, Chen, M, Xu, Y, Wang, Z, Liu, Z, He, C, Zhang, F, Feng, X, Ni, X, Chen, Y, Wang, J, Liang, X, Xie, Z, Li, J, Banach, M, Pelisek, J, Huo, Y, Hu, Y, Evans, PC, Wang, L, Tian, X, Xiao, J, Shang, Y, Zheng, Y, Xian, X, Weng, J & Xu, S 2025, 'A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY', Theranostics, vol. 15, no. 10, pp. 4325-4344. https://doi.org/10.7150/thno.105782

A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY. / Zhang, Zhidan (Co-first Author); Chen, Meijie (Co-first Author); Xu, Yitong (Co-first Author) et al.
In: Theranostics, Vol. 15, No. 10, 2025, p. 4325-4344.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - A natural small molecule isoginkgetin alleviates hypercholesterolemia and atherosclerosis by targeting ACLY

AU - Zhang, Zhidan

AU - Chen, Meijie

AU - Xu, Yitong

AU - Wang, Zhihua

AU - Liu, Zhenghong

AU - He, Chenyang

AU - Zhang, Fanshun

AU - Feng, Xiaojun

AU - Ni, Xiayun

AU - Chen, Yuanli

AU - Wang, Jixia

AU - Liang, Xinmiao

AU - Xie, Zhifu

AU - Li, Jingya

AU - Banach, Maciej

AU - Pelisek, Jaroslav

AU - Huo, Yuqing

AU - Hu, Yunhui

AU - Evans, Paul C.

AU - Wang, Li

AU - Tian, Xiao-yu

AU - Xiao, Jianbo

AU - Shang, Yuhua

AU - Zheng, Yijun

AU - Xian, Xunde

AU - Weng, Jianping

AU - Xu, Suowen

PY - 2025

Y1 - 2025

N2 - 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. © The author(s).

AB - 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. © The author(s).

KW - Atherosclerosis

KW - ATP-Citrate lyase (ACLY)

KW - Hyperlipidemia

KW - Isoginkgetin

KW - lipid metabolism

UR - https://www.scopus.com/pages/publications/105002450715

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-105002450715&origin=recordpage

U2 - 10.7150/thno.105782

DO - 10.7150/thno.105782

M3 - RGC 21 - Publication in refereed journal

C2 - 40225566

SN - 1838-7640

VL - 15

SP - 4325

EP - 4344

JO - Theranostics

JF - Theranostics

IS - 10

ER -

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

Abstract

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

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