Liver regeneration after partial hepatectomy: Triggers and mechanisms

Liver regeneration (LR) following partial hepatectomy (PH) is a unique and complex physiological response that restores hepatic mass and function through tightly orchestrated cellular and molecular events. Traditionally viewed as a proliferation-driven process, LR is now understood to involve both hepatocyte hyperplasia and hypertrophy, triggered primarily by hemodynamic alterations such as increased portal pressure and shear stress. These promote LR through endothelial-hepatocyte communication via activation of Piezo1 - a mechanosensitive ion channel highly expressed in vascular endothelial cells. This channel is considered one of the potential upstream activators of molecular cascades including the interleukin (IL)-6/signal transducer and activator of transcription 3, tumour necrosis factor-alpha/nuclear factor-kappa B, Wnt/β-catenin, Hippo/ YAP, transforming growth factor-beta, and Notch pathways, which contribute variably to the proliferation, differentiation, or suppression of hepatic cells. Novel insights into the IL-22 and IL-33 signaling axes, bile acid and glutamine metabolism, and the role of intestinal microbiota are also presented as promising emerging targets. This review synthesizes current insights into the interplay between mechanical cues, key signaling pathways, and metabolic reprogramming that govern early regenerative responses. We explore the mechanisms dictating the balance between hyperplasia and hypertrophy, noting that hypertrophy predominates after minor resections, while proliferation is dominant in larger resections. Polyploidization emerges as a significant adaptive mechanism, contributing to hepatocyte survival and tissue remodeling. The importance of ductular reactions, microvascular adjustments, and extracellular matrix dynamics in lobular architecture remodeling is also highlighted. The study explores the occurrence of ductular reactions in both minor and major resections, particularly within the granulation tissue near dissection areas. The paper also examines structural remodeling in regenerated liver tissue, demonstrating ongoing transformations in hepatocyte morphology and sinusoidal architecture even months after PH, and emphasizing that the termination of liver mass regrowth does not equate to the cessation of LR.