Kaempferol‑copper complex alleviates oxidative stress and inflammatory response in acute alcoholic liver injury by inhibiting the TLR4/MAPK/NF-κB signaling pathway.

Although alcohol consumption is a major factor contributing to liver damage and inflammation, the development of therapeutic strategies and pharmacological interventions for alcoholic liver disease (ALD) is still in its infancy. Recent research, however, has highlighted individual variability in susceptibility to ALD, and certain treatments, such as GLP1 agonists, have shown promise in mitigating the progression of liver disease in patients with chronic liver conditions. Flavonoids, the most abundant polyphenols in diet, possess a distinctive electron-rich conjugated structure that can significantly enhance the pharmacological activity of metal complexes and even impart novel bioactivities. In this study, kaempferol-metal complexes (Cu/Fe/Zn) were synthesized, with Ka-Cu exhibiting superior antioxidant capacity, warranting further mechanistic evaluation. In models of ethanol-induced liver injury, high-dose Ka-Cu (90 mg/kg) significantly reduced serum levels of aspartate transaminase (AST) and alanine transaminase (ALT) compared to the ethanol-treated group. Furthermore, Ka-Cu enhanced the activities of hepatic superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GSH-Px), while decreasing the extent of hepatic steatosis. Transcriptome sequencing and western blot analysis corroborated that Ka-Cu alleviated liver injury via a dual regulatory mechanism. This mechanism entails inhibition of the TLR4/MAPK/NF-κB inflammatory pathway by downregulating the protein expression of TLR4, MYD88, and phosphorylated p38 MAPK, alongside the augmentation of antioxidant defense through the reduction of malondialdehyde (MDA) levels. These findings propose a novel therapeutic strategy for the application of kaempferol-metal complexes in ALD.