Combination of Cornus officinalis Siebold and Moutan officinalis (L.) Lindl. alleviates the metabolic disorders of MAFLD through regulating IRE1α/ASK1/JNK pathway mediated endoplasmic reticulum stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis Siebold and Moutan officinalis (L.) Lindl. (CM), as a classic herbal combination in Liuwei Dihuang Pill, have been extensively utilized in the treatment of liver and metabolic disorders. Despite their widespread use, the underlying mechanisms by which these herbs exert therapeutic effects in the management of MAFLD remain inadequately understood and warrant further exploration.

AIM OF STUDY: This study aimed to evaluate the effects of CM on MAFLD. The underlying mechanisms were investigated using both in vitro and in vivo models.

METHODS

MAFLD models were constructed with High-fat diet (HFD)-induced mice and free fatty acid (FFA)-induced HepG2 cells in vivo and in vitro. The impact of CM on lipid buildup and liver damage was investigated using histological and biochemical techniques. To identify metabolic abnormalities among groups, metabolomic profiling was carried out. Bioinformatics enrichment and network-pharmacology analyses were then integrated to identify putative molecular pathways. Biochemical method, western blotting and immunofluorescence assays were carried out to verify the predicted molecular.

RESULTS

CM treatment markedly improved hepatic steatosis in MAFLD mice, accompanied by reduced hepatic lipid deposition, decreased inflammatory marker expression, improved metabolic disturbances, decreased serum lipid levels, and alleviated liver injury. In the PA + OA-induced HepG2 cell model, CM also reduced lipid accumulation and inflammatory responses. Mechanistically, CM treatment was associated with reduced activation of ER stress-related IRE1α/ASK1/JNK signaling, as reflected by decreased p-IRE1α, p-ASK1, and p-JNK levels both in vivo and in vitro. In addition, pharmacological inhibition of IRE1α by KIRA6 weakened the regulatory effect of CM in the HepG2 model, suggesting that IRE1α/ASK1/JNK-related signaling may be involved in the protective effect of CM against MAFLD.

CONCLUSION

This study suggests that CM alleviates MAFLD-related metabolic disorders and that this effect may be associated with modulation of IRE1α/ASK1/JNK pathway-related endoplasmic reticulum stress. These findings provide experimental support for the potential therapeutic value of CM in MAFLD.