Glycyrrhizin Attenuates White Matter Injury by Inhibiting Neuroinflammation through the HMGB1/TLR4 Pathway

White matter injury (WMI) is a common complication of preterm birth, potentially resulting in long-term behavioral and motor abnormalities. The objective of this study is to investigate the neuroprotective effects of glycyrrhizin (GLY) on WMI, and try to elucidate the potential mechanisms. In vivo chronic hypoxia-induced WMI mouse model and in vitro oxygen-glucose deprivation (OGD) induced WMI cell model were established, and the effects of GLY on WMI were explored through multiple assays, such as western blotting, immunofluorescence, immunohistochemistry, behavioral experiments, real-time quantitative polymerase chain reaction (RT-qPCR), transmission electron microscope (TEM), molecular docking, and bioinformatics analysis. The results showed that GLY facilitated the maturation and differentiation of oligodendrocytes and enhanced the thickness as well as density of myelin sheaths. GLY also reduced inflammatory response, improved memory, learning, and locomotor performances, and alleviated anxiety in WMI mice. The neuroprotective effects of GLY may be involved in the down-regulation of HMGB1 and its associated proteins such as TLR4 and NF-κB. In conclusion, GLY could mitigate chronic hypoxia-induced WMI and OGD-induced oligodendrocyte injury through its anti-inflammatory effects by inhibiting the HMGB1/TLR4 pathway, suggesting a potential therapeutic avenue for WMI.