Liver regeneration: cytokine regulation targeting hepatocytes and beyond

The liver, the largest glandular organ in humans, exhibits a unique and robust regenerative capacity following injury. This regenerative response is orchestrated through a highly regulated network of cellular and molecular signals. Here, we review the cytokine-mediated regulation of liver regeneration, emphasizing autocrine, paracrine, as well as endocrine pathways. Hepatocyte proliferation is modulated not only by intrinsic signals but also by cytokines derived from non-parenchymal cells–including Kupffer cells, hepatic stellate cells, and liver sinusoidal endothelial cells–as well as by endocrine cues from the systemic circulation. From the perspective of metabolic reprogramming, these regulatory pathways illustrate how adaptive changes in glucose, lipid, and amino acid metabolism collectively sustain the cellular activities essential for liver regeneration. We further explore how metabolic adaptations contribute to regeneration, providing mechanistic insights and revealing potential therapeutic targets for liver diseases. Finally, we discuss emerging strategies that target cytokine networks and metabolic pathways to enhance liver regeneration, highlighting recent advances in translational applications.