Lycium barbarum polysaccharides and melatonin alleviate cadmium-induced hepatic metabolic injury associated with alterations in PI3K/AKT signaling.

Lycium barbarum polysaccharides (LBP), bioactive macromolecules derived from Lycium barbarum, exhibit metabolic regulatory and hepatoprotective activities. Cadmium (Cd) exposure is a major environmental concern associated with hepatic metabolic dysfunction and liver injury; however, the potential protective role of LBP against Cd-induced hepatic dysfunction and the effects of its combined administration with melatonin (MT) remain incompletely understood. In this study, we investigated the protective effects of LBP, alone or in combination with MT, in a mouse model of chronic Cd exposure. Cd exposure induced pronounced liver injury, accompanied by impaired insulin sensitivity, glucose intolerance, and increased hepatic PI3K/AKT phosphorylation. LBP treatment alleviated Cd-induced metabolic disorders and attenuated Cd-induced aberrant PI3K/AKT phosphorylation, with these effects further enhanced by combined treatment with MT, including improved insulin sensitivity, normalized lipid profiles, preserved mitochondrial integrity, suppressed inflammatory responses, and reduced fibrotic progression. Furthermore, in vitro experiments demonstrated that pharmacological inhibition of PI3K with LY294002 attenuated Cd-induced loss of cell viability and inflammatory responses in AML12 cells, supporting the involvement of PI3K-related signaling in Cd-induced hepatocellular injury. Collectively, these findings indicate that LBP and/or MT alleviate Cd-induced hepatic metabolic injury, while reducing PI3K/AKT phosphorylation. This study provides experimental evidence for the potential mitigating effects of LBP and/or MT-based interventions against Cd-associated hepatic metabolic injury.