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 (HQFs) by constructing pseudonatural flavonols, which possess flavonoid bioactivity and enhanced copper transport properties. In cell models and mice, we found that HQF-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.