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The liver is the only vertebrate organ capable of regenerating after injury, infection, or partial surgical removal. Approximately 80% of liver mass consists of hepatocytes—cells responsible for most liver functions. These cells remain dormant in the G0 phase of the cell cycle until stimulated by injury signals, allowing them to proliferate and restore organ mass and tissue architecture.

Kupffer cells are specialized phagocytic cells lining liver capillaries that respond to injury by releasing cytokines IL-6 and TNF-α. These cytokines prime hepatocytes to express c-MET and EGF receptors on their cell surface, making them receptive to growth factors. This priming phase is essential for triggering hepatocyte proliferation and initiating the regeneration process.

Stellate cells and the duodenum release hepatocyte growth factor (HGF) and epidermal growth factor (EGF), which enter the injury site through the bloodstream. These growth factors bind to c-MET and EGFR receptors on primed hepatocytes, enabling them to overcome the G0/G1 cell cycle checkpoint and begin proliferating to heal damaged tissue.

The liver comprises four major cell types: hepatocytes store glycogen and vitamins; stellate cells store vitamin A; Kupffer cells are specialized macrophages that kill bacteria and remove aged red blood cells; and sinusoidal endothelial cells form blood vessel walls. Each cell type contributes distinct functions essential to liver metabolism and immune defense.

Once the liver reaches its necessary size and tissue architecture is restored, stellate cells release transforming growth factor-beta (TGF-β). This cytokine blocks hepatocyte proliferation and terminates the regeneration process, preventing excessive growth and maintaining organ homeostasis and proper liver function.

Beyond HGF and EGF, insulin from the pancreas, norepinephrine from the adrenal gland, and triiodothyronine from the thyroid gland facilitate hepatocytes in overcoming the G0/G1 checkpoint. These hormonal signals work synergistically with growth factors to enable hepatocytes to enter the S phase and proliferate during regeneration.

Liver regeneration involves three organized phases: the priming phase, where cytokines prime hepatocytes; the proliferative phase, where growth factors trigger hepatocyte proliferation and tissue restoration; and the termination phase, where TGF-β halts proliferation. This coordinated process ensures controlled regeneration and restoration of liver function.