Liquiritigenin Alleviates Hepatic Metabolic Inflammation Through Regulation of Muscle–Liver Crosstalk Signal of Myonectin

Liquiritigenin (LQ), a flavonoid derived from the roots of licorice, exhibits diverse biological activities. However, the specific role of LQ in alleviating non‐alcoholic fatty liver disease (NAFLD) and its correlated metabolic disorders remains to be further explored. This study aimed to investigate the effects and molecular mechanisms of LQ in modulating metabolic inflammation (meta‐inflammation) and mainly focused on a systemic muscle–liver crosstalk mediated by myonectin. High‐fat diet (HFD) male C57BL/6J mice were established to evaluate the effects of LQ on hepatic lipid accumulation, inflammation and secretion of myonectin. The effects of LQ and myonectin on meta‐inflammation and the potential molecular mechanisms in vitro were assessed in C2C12 cells and HepG2 cells. In vivo findings indicated that LQ attenuated HFD‐induced hepatic steatosis and meta‐inflammation. LQ treatment downregulated the meta‐inflammation‐related protein expression levels of CD36 and TLR4, subsequently reducing the phosphorylation levels of c‐Jun N‐terminal kinase (JNK), c‐jun, and NF‐κB. Administration of LQ was associated with reduced levels of myonectin. Myonectin and PA exhibited synergistic effects on enhancing protein expressions of the CD36/TLR4 pathway, whereas LQ attenuated the activation of these protein expressions. Additionally, a pretreatment with LPS eliminated the protective effects of LQ and restored the effects of PA and myonectin. The mechanisms of LQ on reducing meta‐inflammation might be mediated by muscle–liver crosstalk signaling of myonectin, and the CD36/TLR4 signaling pathway was essential in modulating meta‐inflammation by LQ. These findings demonstrated the role and mechanisms of LQ in alleviating meta‐inflammation, which was mediated through muscle–liver crosstalk signals of myonectin and its downstream CD36/TLR4 pathway. The results would provide novel insights into the potential of LQ as a phytotherapy for NAFLD.