Rebamipide Reprograms Hepatic Networks to Prevent and Reverse Metabolic-Dysfunction-Associated Steatotic Liver...

Area of Science:

• Hepatology and Metabolic Diseases
• Pharmacology and Drug Discovery
• Proteomics and Systems Biology

Background:

• Metabolic-dysfunction-associated steatotic liver disease (MASLD) presents a significant global health challenge with no current approved drug therapies.
• Investigating novel therapeutic agents is crucial for managing this growing condition.

Purpose of the Study:

• To evaluate the potential of Rebamipide, an anti-inflammatory drug, in preventing and treating MASLD.
• To utilize a high-fat diet-induced MASLD rat model combined with advanced proteomics and network analysis.

Main Methods:

• Male Wistar rats were subjected to a high-fat diet (MHFD) for 16 weeks, with Rebamipide administered either prophylactically or therapeutically.
• Label-free LC-MS/MS proteomics, principal component analysis (PCA), PLS-DA, and pathway enrichment analyses (GO, KEGG, Reactome) were employed.
• Histopathological examination assessed liver damage and structural normalization.

Main Results:

• MHFD induced significant suppression of mitochondrial chaperones (Hspa9), Mttp, and Cyp2c6, disrupting lipid handling and oxidative stress defense.
• Rebamipide prophylaxis preserved lipid metabolism and antioxidant functions; therapeutic administration reversed steatosis and enhanced fatty acid oxidation and detoxification.
• Key proteins Mttp, Cyp2c6, and Hspa9 were identified as central to Rebamipide's effects, modulating lipid transport, protein import, and stress adaptation.

Conclusions:

• Rebamipide exhibits a dual-phase mechanism, offering early protection against diet-induced liver injury and effectively reversing established MASLD.
• The study identifies a core protein triad (Mttp, Cyp2c6, Hspa9) and related pathways, suggesting novel therapeutic targets and biomarkers for MASLD.
• Findings support the repurposing of Rebamipide as a potential pharmacological treatment for metabolic liver diseases.