Liquiritin restores metabolic homeostasis in NAFLD by modulating AKT1/FOXO1 signaling.

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition with a complex and multifactorial pathogenesis.

PURPOSE: This study aimed to investigate the mecha-nism of liquiritin (LQ) in NAFLD for its treatment.

METHODS

This study integrates bioinformatics analysis with in vitro validation. Bulk RNA-seq analysis and single-cell dataset analysis were performed using Gene Expression Omnibus database resources. Molecular docking and molecular dynamics simulations were employed to evaluate the binding affinity of liquiritin with lipid metabolism-related proteins AKT and FOXO1. In vitro validation was conducted using the HepG2, AML12 and RAW 264.7 to investigate the mechanism by which liquiritin regulates lipid metabolic homeostasis in HepG2 cells and AML12 cells via the AKT/FOXO1 pathway through protein immunoblotting and immunofluorescence. The effects of liquiritin on mitochondrial autophagy in RAW 264.7 cells were also examined.

RESULTS

Bulk RNA-seq analysis identified FOXO1 as a key target, while single-cell analysis predicted interactions between hepatocytes and macrophages in non-alcoholic fatty liver disease (NAFLD). Molecular docking predicted a potential stable interaction between liquiritin and FOXO1. In HepG2 cells and AML12 cells, liquiritin improved NAFLD lipid metabolism disorders by regulating the AKT/FOXO1 pathway. Liquiritin also modulates the expression of mitophagy-associated proteins in RAW264.7 cells.

CONCLUSION

Liquiritin improves lipid metabolism disorders in NAFLD by regulating the AKT/FOXO1 pathway, while also potentially influencing macrophage function. This suggests its potential as a candidate therapeutic agent for non-alcoholic fatty liver disease.