Pseudonatural Flavonols as Novel Copper Ionophores for NAFLD Intervention via Synergistic Copper Delivery and Flavonoid Activity
Copper plays crucial roles in fundamental life processes, including proliferation, metabolism, and survival. Copper deficiency is associated with multiple diseases, such as nonalcoholic fatty liver disease (NAFLD) and Wilson's disease. Therapeutic programs targeting copper supply are prospectively employed for disease intervention. Herein, we developed biofriendly copper ionophores (<b>HQFs</b>) by constructing pseudonatural flavonols, which possess flavonoid bioactivity and enhanced copper transport properties. In cell models and mice, we found that <b>HQF</b>-mediated copper delivery synergistically, safely, and efficiently intervened in the development of fatty liver. Mechanistically, NAFLD remission involves fatty acid metabolism, anti-inflammatory processes, and pentose phosphate pathway (PPP) enhancement. Our work is the first to propose the utilization of synergistic copper loading and flavonoid activity for NAFLD intervention, which may inform the clinical management of liver disease.
Authors
- Weiqin Zhang
- Liuxin Yang (ORCID: https://orcid.org/0009-0007-9696-120X)
- Ying Yang (ORCID: https://orcid.org/0000-0002-1871-3119)
- Shao Zhong (ORCID: https://orcid.org/0000-0002-9054-6554)
- Muqing Shao
- Fang Wang (ORCID: https://orcid.org/0000-0001-5643-7920)
- Xiang Li (ORCID: https://orcid.org/0000-0003-0356-4066)
- Gang Chen (ORCID: https://orcid.org/0009-0008-3455-4956)
- Kai You Wang (ORCID: https://orcid.org/0000-0002-6170-4744)
- Qin Li (ORCID: https://orcid.org/0000-0001-9985-7861)
- Shuang Qiu (ORCID: https://orcid.org/0000-0002-8327-2567)
- Jingfang Yang
- Jun Jiang (ORCID: https://orcid.org/0000-0003-3401-792X)
- Qin Si
- Chen Jiang (ORCID: https://orcid.org/0000-0001-6852-7755)
- Man Li (ORCID: https://orcid.org/0009-0003-9777-2874)
Institutions
- Institute of Plant Protection (CN)
- Hubei University of Science and Technology (CN)
- Culture Resource (EG)
- Wuhan Textile University (CN)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Chinese Academy of Agricultural Sciences (CN)
- State Key Laboratory of Biology of Plant Diseases and Insect Pests
- Northeast Forestry University (CN)
- Kitware (United States) (US)
- Hubei University (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-03-13
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02927
- Citations
- 5
- Primary Topic
- Trace Elements in Health
- Type
- article
- Field-Weighted Citation Impact
- 5.60
Funders
- China Postdoctoral Science Foundation
- Natural Science Foundation of Hubei Province
- Chongqing Municipal Education Commission