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Cholesterol Efflux Assay
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Cholesterol Efflux Assay

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

Zhidan Zhang1, Meijie Chen1, Yitong Xu2

  • 1Department 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.

Theranostics
|April 14, 2025
PubMed

Insights

A natural compound, isoginkgetin (ISOGK), inhibits ATP citrate lyase (ACLY) to lower cholesterol and reduce atherosclerosis. This discovery offers a promising new avenue for cardiovascular therapeutics.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Cardiovascular Research

Background:

  • Atherosclerotic cardiovascular disease (ASCVD) is a leading global cause of death.
  • Hypercholesterolemia is a major risk factor for ASCVD.
  • ATP citrate lyase (ACLY) is a key enzyme in cholesterol biosynthesis and a potential drug target.

Purpose of the Study:

  • To identify novel small-molecule inhibitors of ACLY from natural products.
  • To evaluate the lipid-lowering and anti-atherosclerotic potential of identified compounds.
  • To elucidate the mechanism of action of promising drug candidates.

Main Methods:

  • Virtual screening of a natural product library identified isoginkgetin (ISOGK) as an ACLY inhibitor.
  • ISOGK's inhibitory activity was confirmed using enzymatic assays, SPR, and CETSA.
  • Lipid-lowering and anti-atherosclerotic effects were assessed in animal models (mice, hamsters), including liver-specific ACLY knockdown models.

Main Results:

  • Isoginkgetin (ISOGK) directly inhibits ACLY activity both in vitro and in vivo.
  • ISOGK treatment reduced hypercholesterolemia and atherosclerosis in animal models.
  • The therapeutic effects of ISOGK were dependent on hepatic ACLY expression, as shown by knockdown studies.

Conclusions:

  • Isoginkgetin (ISOGK) is a potent, naturally-derived ACLY inhibitor.
  • ISOGK effectively mitigates hypercholesterolemia and atherosclerosis.
  • ISOGK represents a promising therapeutic lead for cardiovascular diseases.

Keywords:
ATP-Citrate lyase (ACLY)AtherosclerosisHyperlipidemiaIsoginkgetinlipid metabolism

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