Hepatic Transcriptome and Its Regulation Following Soluble Epoxide Hydrolase Inhibition in Alcohol-Associated Liver...

Area of Science:

• Hepatology
• Pharmacology
• Biochemistry

Background:

• Alcohol-associated liver disease (ALD) presents a significant public health challenge with limited pharmaceutical interventions.
• Soluble epoxide hydrolase (sEH) plays a role in lipid metabolism and is a potential therapeutic target.

Purpose of the Study:

• To evaluate the efficacy of pharmacologic sEH inhibition using TUCB in a mouse model of ALD.
• To elucidate the underlying mechanisms by which sEH inhibition impacts liver injury.

Main Methods:

• Mice were subjected to acute-on-chronic ethanol (EtOH) feeding, with or without the sEH inhibitor TUCB.
• Liver injury was assessed using multiple endpoints, including plasma alanine aminotransferase levels.
• Metabolomic analysis of liver fatty acids and RNA sequencing were performed.

Main Results:

• TUCB treatment significantly ameliorated EtOH-induced liver injury, indicated by reduced liver enzymes.
• TUCB attenuated endoplasmic reticulum stress, decreased neutrophil infiltration, and promoted M2 macrophage polarization in the liver.
• Transcriptomic analysis revealed that TUCB altered lipid metabolism and downregulated genes associated with apoptosis, inflammation, fibrosis, and carcinogenesis.

Conclusions:

• Pharmacologic inhibition of sEH with TUCB demonstrates significant therapeutic benefits in experimental ALD.
• sEH inhibition modulates key pathways involved in liver injury, inflammation, and disease progression.
• These findings highlight the translational potential of targeting sEH for ALD treatment.