The objective of this study is to examine the potential protective effect of rosmarinic acid (RosA) encapsulated within nanoliposomes (RosA-LIP) on hepatic damage induced by iron overload. The characteristics, stability, and release of RosA-LIP in vitro were identified. The mice were randomly assigned to five groups: Control, Model, Model+DFO (DFO), Model+RosA (RosA), and Model+RosA-LIP (RosA-LIP). The iron overload model was induced by administering iron dextran (i.p.). The DFO, RosA, and RosA-LIP groups received iron dextran and were subsequently treated with DFO, RosA, and RosA-LIP for 14 days. We developed a novel formulation of RosA-LIP that exhibited stability and controlled release properties. Firstly, RosA-LIP improved liver function and ameliorated pathological changes in a mouse model of iron overload. Secondly, RosA-LIP demonstrated the ability to enhance the activities of T-SOD, GSH-Px, and CAT, while reducing the levels of MDA and 4-HNE, thereby effectively mitigating oxidative stress damage induced by iron overload. Thirdly, RosA-LIP reduced hepatic iron levels by downregulating FTL, FTH, and TfR1 levels. Additionally, RosA-LIP exerted a suppressive effect on hepcidin expression through the BMP6-SMAD1/5/8 signaling pathway. Furthermore, RosA-LIP upregulated FPN1 expression in both the liver and duodenum, thereby alleviating iron accumulation in these organs in mice with iron overload. Notably, RosA exhibited a comparable iron chelation effect, and RosA-LIP demonstrated superior efficacy in mitigating liver damage induced by excessive iron overload. RosA-LIP exhibited favorable sustained release properties, targeted delivery, and efficient protection against iron overload-induced liver damage. A schematic representation of the proposed protective mechanism of rosmarinic acid liposome during iron overload. Once RosA-LIP is transported into cells, RosA is released. On the one hand, RosA attenuates the BMP6-SMAD1/5/8-SMAD4 signaling pathway activation, leading to inhibiting hepcidin transcription. Then, the declined hepcidin contacted the inhibitory effect of FPN1 in hepatocytes and duodenum, increasing iron mobilization. On the other hand, RosA inhibits TfR1 and ferritin expression, which decreases excessive iron and oxidative damage.
