Targeting Egfr-Mediated Cell Proliferation and Lipid Metabolism Separation Effectively Accelerate Liver Regeneration

Area of Science:

• Hepatology
• Molecular Biology
• Metabolic Research

Background:

• Hepatocyte proliferation restores liver mass after partial hepatectomy (PHx).
• The metabolic cost of liver regeneration remains poorly understood.
• Understanding metabolic shifts is crucial for improving post-surgical liver recovery.

Purpose of the Study:

• To investigate the metabolic changes during liver regeneration after PHx.
• To identify molecular mechanisms linking hepatocyte proliferation and lipid metabolism.
• To explore therapeutic strategies for enhancing liver regeneration.

Main Methods:

• Single-nucleus transcriptomics was performed on mouse liver samples 48 hours after 70% PHx.
• Analysis focused on the interplay between epidermal growth factor receptor (EGFR)-FOXM1 signaling and peroxisome proliferator-activated receptor alpha (PPARα)-acyl-CoA synthetase 1 (ACSL1) pathway.
• Pharmacological activation of PPARα using Wy-14643 was employed to assess its impact on liver regeneration.

Main Results:

• EGFR-FOXM1 signaling drives hepatocyte mitotic entry while suppressing PPARα-ACSL1-mediated lipid catabolism.
• Triglycerides and free fatty acids accumulate in regenerating liver tissue.
• Activating PPARα with Wy-14643 released the metabolic brake, accelerated proliferation via HIF1α-FOXM1, and improved post-PHx recovery.

Conclusions:

• Lipid-metabolic reprogramming is an EGFR-dependent consequence of liver regeneration.
• Pharmacological activation of PPARα can reverse this metabolic suppression and enhance liver regeneration.
• This strategy holds potential for reducing post-operative liver failure and hospital stay in surgical patients.