Multi-omics mechanistic studies for curcumin-mediated intracellular copper release to alleviate MAFLD

Metabolic dysfunction-associated fatty liver disease (MAFLD) is increasingly prevalent worldwide. While curcumin (Cur) has shown promise in managing MAFLD, its clinical translation is hindered by poor bioavailability. Additionally, optimal copper (Cu) intake has been shown to delay MAFLD progression. Notably, Cur can function as a natural Cu ionophore, forming a bioactive Cur-Cu complex that enhances cellular Cu delivery and improves the bioavailability of Cur. This study aimed to explore the potential effects of Cur-Cu on the alleviation of hepatic steatosis and to dissect the underlying molecular mechanisms. Using both cellular and murine models, we evaluated the protective effects of Cur-Cu against MAFLD progression. To explore potential therapeutic targets of Cur-Cu, RNA sequencing was performed on palmitic acid-treated HepG2 cells, complemented by hepatic proteomic and metabolomic analyses in high-fat diet-induced mice. Cur-Cu showed relatively stronger inhibition of intracellular lipid accumulation in cell models than Cur or Cu alone, and alleviated hepatic steatosis in a murine MAFLD model. In vivo, the complex partially restored hepatic non-esterified fatty acids and improved the circulating lipid profile. Mechanistically, multi-omics analyses revealed potential associations between these phenotypic changes and the suppression of hepatic inflammation, the scavenging of reactive oxygen species, the reduction of fatty acid levels, and the enhancement of tricarboxylic acid cycle flux. Collectively, these findings suggest that the metal-polyphenol complex Cur-Cu may exert multiple protective effects against MAFLD via diverse mechanisms. This study offers preliminary evidence supporting Cur-Cu as a potential candidate for developing adjuvant therapeutic strategies in MAFLD management. Notably, the comparative superiority of the complex over Cur or Cu alone was observed in our in vitro cellular model, but dedicated head-to-head animal studies are required to confirm such superiority in vivo.