Nonalcoholic steatohepatitis (NASH) is a critical stage in the progression of nonalcoholic fatty liver disease (NAFLD). Tanshinone IIA (TIIA) is a tanshinone extracted from Salvia miltiorrhiza; due to its powerful anti-inflammatory and antioxidant biological activities, it is commonly used for treating cardiovascular and hepatic diseases. A NASH model was established by feeding mice a methionine and choline-deficient (MCD) diet. Liver surface microblood flow scanning, biochemical examination, histopathological examination, cytokine analysis through ELISA, lipidomic analysis, transcriptomic analysis, and Western blot analysis were used to evaluate the therapeutic effect and mechanism of TIIA on NASH. The results showed that TIIA effectively reduced lipid accumulation, fibrosis, and inflammation and alleviated endoplasmic reticulum (ER) stress. Lipidomic analysis revealed that TIIA normalized liver phospholipid metabolism in NASH mice. A KEGG analysis of the transcriptome revealed that TIIA exerted its effect by regulating the PPAR signalling pathway, protein processing in the ER, and the NOD-like receptor signalling pathway. These results suggest that TIIA alleviates NASH by activating the PPARα/FGF21 axis to negatively regulate the ER stress-induced unfolded protein response (UPR).

Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), which is distinguished by the accumulation of fat in the liver, damage to liver cells, and inflammation. Chaihu Shugan powder (CSP), a renowned traditional Chinese medicine (TCM) blend extensively utilized in China to address liver disease, has demonstrated its efficacy in reducing lipid buildup and effectively combating inflammation. Hence, the primary objective of this research is to examine the impacts and possible mechanisms of CSP on NASH through assessments of liver histopathology, lipidomic analysis, and gene expression. To induce a mouse model of NASH, we employed a diet which deficient in methionine and choline, known as methionine–choline deficient (MCD) diet. Initially, we examined the impact of administering CSP to NASH mice by assessing the levels of serum and liver indicators. We found that CSP was able to reduce lipid buildup and inflammation in mice. In addition, a total of 1009 genes exhibited enrichment in both the autophagy and ferroptosis pathways. The liver protein levels of Adenosine monophosphate‐activated protein kinase–mammalian target of rapamycin (AMPK–mTOR)‐mediated autophagy and ferroptosis markers, such as p‐AMPKα/AMPKα, p‐mTOR/mTOR, Beclin‐1, microtubule associated protein 1 light chain 3 gamma (LC3), p62 (sequestosome 1 [SQSTM1/p62]), Kelch‐like ECH‐associated protein 1 (KEAP1), nuclear factor erythroid 2‐related factor 2 (Nrf‐2), ferritin heavy chain 1 (FTH1), and glutathione peroxidase 4 (GPX4), were restored by CSP. Furthermore, our findings indicated that the suppression of autophagy had a repressive impact on the occurrence of ferroptosis in the mouse model, indicating that autophagy activation likely plays a role in mediating ferroptosis in NASH.

Leonurine is a natural product unique to the Lamiaceae plant Leonurus japonicus Houtt., and it has attracted attention due to its anti-oxidative stress, anti-apoptosis, anti-fibrosis, and metabolic regulation properties. Also, it plays an important role in the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) through a variety of biological mechanisms, but its mechanism of action remains to be elucidated. Therefore, this study aims to preliminarily explore the mechanisms of action of leonurine in NAFLD. Mice were randomly divided into four groups: the normal control (NC) group, the Model (M) group, the leonurine treatment (LH) group, and the fenofibrate treatment (FB) group. The NAFLD model was induced by a high-fat high-sugar diet (HFHSD) for 12 weeks, and liver pathological changes and biochemical indices were observed after 12 weeks. Transcriptomic analysis results indicated that leonurine intervention reversed the high-fat high-sugar diet-induced changes in lipid metabolism-related genes such as stearoyl-CoA desaturase 1 (Scd1), Spermine Synthase (Sms), AP-1 Transcription Factor Subunit (Fos), Oxysterol Binding Protein Like 5 (Osbpl5), and FK506 binding protein 5 (Fkbp5) in liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results suggest that leonurine may exert its lipid-lowering effects through the AMP-activated protein kinase (AMPK) signaling pathway. Liver lipidomic analysis showed that leonurine could alter the abundance of lipid molecules related to fatty acyl (FAs) and glycerophospholipids (GPs) such as TxB3, carnitine C12-OH, carnitine C18:1-OH, and LPC (20:3/0:0). Molecular biology experiments and molecular docking techniques verified that leonurine might improve hepatic lipid metabolism through the alpha-1A adrenergic receptor (ADRA1a)/AMPK/SCD1 axis. In summary, the present study explored the mechanism by which leonurine ameliorated NAFLD by inhibiting hepatic lipid synthesis via the ADRA1a/AMPK/SCD1 axis.

Nonalcoholic steatohepatitis (NASH) is a form of chronic liver disease that is characterized by liver inflammation and steatosis, with possible progression to fibrosis. Currently, no drugs have been approved for the treatment of NASH. In this study, we isolated a polysaccharide from Atractylodes lancea rhizome (AP) and established a methionine- and choline-deficient (MCD) diet -induced NASH mouse model to investigate the preventive effect and potential mechanism of AP on NASH. The results showed that AP effectively reduced liver lipid accumulation and inflammation and reduced autophagy and ferroptosis in hepatocytes, thereby preventing the development of NASH. These findings suggest that AP may be a promising natural candidate for the treatment of NASH.