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Mefunidone ameliorates acute liver failure in mice by inhibiting MKK4-JNK pathway
Yanqiu Zhang1, Xin He2, Lei Gu1
1Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha 410008, China; Hunan Key Lab of Organ Fibrosis, Changsha 410008, China; National International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital, Central South University, Changsha 410008, China.
Abstract:
Acute liver failure (ALF) is a critical condition that can lead to substantial liver dysfunction. It is characterized by complex clinical manifestations and rapid progression, presenting significant challenges in diagnosis and treatment. We investigated the protective effect of mefunidone (MFD), a novel antifibrosis pyridone agent, on ALF in mice, and explored its potential mechanism of action. MFD pretreatment can alleviate lipopolysaccharide (LPS) and d-galactosamine (D-GalN)-induced ALF, reduce hepatocyte apoptosis, and reduce inflammation and oxidative stress. Additionally, MFD alleviated LPS/D-GalN-stimulated reactive oxygen species (ROS) production and cell death in AML12 cells. RNA sequencing enrichment analysis showed that MFD significantly affected the Mitogen-Activated Protein Kinase (MAPK) pathway. In vivo and in vitro experiments showed that MFD inhibited MKK4 and JNK phosphorylation. JNK activation caused by MKK4 and JNK activators could eliminate the therapeutic effect of MFD on AML12. In addition, MFD pretreatment alleviated ConA-induced ALF, reduced inflammation and oxidative stress in mice, and reduced mouse mortality. These results suggest that MFD can potentially protect against ALF, partially by inhibiting the MKK4-JNK pathway, and is a promising new therapeutic drug for ALF.
Insights
Mefunidone (MFD) shows protective effects against acute liver failure (ALF) by reducing liver damage, inflammation, and cell death. It works by inhibiting the MKK4-JNK pathway, suggesting MFD as a potential therapeutic for ALF.
Area of Science:
- Hepatology
- Pharmacology
- Molecular Biology
Background:
- Acute liver failure (ALF) is a severe condition with high mortality and limited treatment options.
- Understanding the molecular mechanisms underlying ALF is crucial for developing effective therapies.
- Novel antifibrotic agents are being explored for their potential in managing liver diseases.
Purpose of the Study:
- To investigate the protective effects of mefunidone (MFD) against ALF in a mouse model.
- To elucidate the underlying mechanism of MFD's action in ALF.
- To evaluate MFD as a potential therapeutic agent for ALF.
Main Methods:
- Induction of ALF using lipopolysaccharide (LPS)/d-galactosamine (D-GalN) and concanavalin A (ConA) in mice.
- Assessment of liver injury markers, hepatocyte apoptosis, inflammation, and oxidative stress.
- In vitro studies using AML12 cells to investigate reactive oxygen species (ROS) production and cell death.
- RNA sequencing to analyze the effect of MFD on cellular pathways, focusing on the Mitogen-Activated Protein Kinase (MAPK) pathway.
- Inhibition of MKK4 and JNK phosphorylation by MFD was confirmed.
Main Results:
- MFD pretreatment significantly alleviated LPS/D-GalN-induced ALF, reducing hepatocyte apoptosis, inflammation, and oxidative stress.
- MFD decreased ROS production and cell death in AML12 cells stimulated with LPS/D-GalN.
- RNA sequencing identified the MAPK pathway as a key target of MFD.
- MFD inhibited MKK4 and JNK phosphorylation, and JNK activation reversed MFD's protective effects.
- MFD also alleviated ConA-induced ALF, reducing inflammation, oxidative stress, and mortality in mice.
Conclusions:
- Mefunidone (MFD) demonstrates significant protective effects against experimental models of acute liver failure.
- MFD's mechanism involves the inhibition of the MKK4-JNK signaling pathway, mitigating inflammation and oxidative stress.
- MFD is a promising novel therapeutic candidate for the treatment of acute liver failure.
