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

Hepatocyte proliferation restores liver mass after partial hepatectomy (PHx), but the metabolic cost of this process remains unclear. Single-nucleus transcriptomics of mouse liver 48 h after 70% PHx revealed that EGFR-FOXM1 signalling drives mitotic entry while simultaneously suppressing PPARα-ACSL1-mediated lipid catabolism. Consequently, triglycerides and free fatty acids accumulate in regenerating tissue. Activating PPARα with the agonist Wy-14643 released this metabolic brake, accelerated hepatocyte proliferation via HIF1α-FOXM1, and improved post-PHx recovery. These data identify lipid-metabolic reprogramming as an EGFR-dependent collateral effect that can be pharmacologically reversed to enhance liver regeneration in surgical patients, offering a readily translatable strategy to reduce post-operative liver failure and shorten hospital stay after major hepatectomy.