Kaempferol Mitigates Liver Injury Induced by Copper Toxicity Through the Activation of the Sirt1/Nrf2/FOXO3 Signaling Pathway

Excessive copper (Cu) accumulation induces hepatotoxicity, while the natural flavonoid kaempferol (KA) exhibits potent antioxidant and anti-inflammatory activities. This study explored the protective effects of kaempferol against copper overload-induced liver injury in rats and the underlying molecular mechanisms. A copper overload model was established in Sprague-Dawley (SD) rats through the administration of copper sulfate (CuSO₄) over 12 weeks, followed by kaempferol intervention. Comprehensive evaluations were conducted on hepatic copper accumulation, liver function indices, histopathological alterations, and associated molecular pathways. Western blot analysis demonstrated that kaempferol mitigated copper-induced liver damage by upregulating Sirt1, which subsequently activated the Nrf2/FOXO3 signaling pathway, thereby reducing oxidative stress, inflammation, and hepatocyte apoptosis. Metabolomics analysis further revealed that kaempferol influenced metabolic pathways, including lysine degradation and cysteine-methionine metabolism, indicating its multi-target and multi-pathway regulatory effects. In conclusion, kaempferol mitigates copper-induced liver injury through complex molecular networks, providing novel insights into therapeutic approaches for liver diseases associated with copper metabolism and underscoring the multi-mechanistic potential of natural compounds.