As a research hotspot in the field of regenerative medicine, hepatocyte regeneration has great potential in the treatment of liver diseases. This paper comprehensively summarizes the diverse sources of hepatocyte regeneration and its complex influencing factors, and deeply discusses the typical mechanism. According to the existing research, we observed that Wnt signaling pathway and Notch signaling pathway can play a synergistic role in the process of hepatocyte regeneration. So we further analyzed the crosstalk between Wnt and Notch signal pathway and the cross mechanism with TGF-β, YAP/TAZ pathway during regeneration. Despite the remarkable progress in the study of liver regeneration at the cellular and molecular levels, the comprehensive understanding of the fine regulation of influencing factors and the interaction between mechanisms still needs to be deepened. This paper aims to systematically analyze the interaction between influencing factors and classical mechanisms of hepatocyte regeneration by integrating multi-group data and advanced bioinformatics methods, so as to provide feasible ideas for the treatment of liver diseases and lay a solid theoretical foundation for the future development of regenerative medicine. It is believed that focusing on the rational development of innovative means such as inducing gene tendentiousness expression and anti-aging therapy, and in-depth analysis of the complex interactive network between hepatocyte regeneration mechanisms are expected to open up a new road for the development of more effective treatment strategies for liver diseases.

Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.

The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.

Rapid regeneration of the residual liver is one of the key determinants of successful partial hepatectomy (PHx). At present, there is a lack of recognized safe, effective, and stable drugs to promote liver regeneration. It has been reported that vagus nerve signaling is beneficial to liver regeneration, but the potential mechanism at play here is not fully understood.

To explore the effect and mechanism of hepatic vagus nerve in liver regeneration after PHx.

A PHx plus hepatic vagotomy (Hv) mouse model was established. The effect of Hv on liver regeneration after PHx was determined by comparing the liver regeneration levels of the PHx-Hv group and the PHx-sham group mice. In order to further investigate the role of interleukin (IL)-22 in liver regeneration inhibition mediated by Hv, the levels of IL-22 in the PHx-Hv group and the PHx-sham group was measured. The degree of liver injury in the PHx-Hv group and the PHx-sham group mice was detected to determine the role of the hepatic vagus nerve in liver injury after PHx.

Compared to control-group mice, Hv mice showed severe liver injury and weakened liver regeneration after PHx. Further research found that Hv downregulates the production of IL-22 induced by PHx and blocks activation of the signal transducer and activator of transcription 3 (STAT3) pathway then reduces the expression of various mitogenic and anti-apoptotic proteins after PHx. Exogenous IL-22 reverses the inhibition of liver regeneration induced by Hv and alleviates liver injury, while treatment with IL-22 binding protein (an inhibitor of IL-22 signaling) reduce the concentration of IL-22 induced by PHx, inhibits the activation of the STAT3 signaling pathway in the liver after PHx, thereby hindering liver regeneration and aggravating liver injury in PHx-sham mice.

Hv attenuates liver regeneration after hepatectomy, and the mechanism may be related to the fact that Hv downregulates the production of IL-22, then blocks activation of the STAT3 pathway.

The liver serves as a vital regulatory hub for various physiological processes, including sugar, protein, and fat metabolism, coagulation regulation, immune system maintenance, hormone inactivation, urea metabolism, and water-electrolyte acid-base balance control. These functions rely on coordinated communication among different liver cell types, particularly within the liver's fundamental hepatic lobular structure. In the early stages of liver development, diverse liver cells differentiate from stem cells in a carefully orchestrated manner. Despite its susceptibility to damage, the liver possesses a remarkable regenerative capacity, with the hepatic lobule serving as a secure environment for cell division and proliferation during liver regeneration. This regenerative process depends on a complex microenvironment, involving liver resident cells, circulating cells, secreted cytokines, extracellular matrix, and biological forces. While hepatocytes proliferate under varying injury conditions, their sources may vary. It is well-established that hepatocytes with regenerative potential are distributed throughout the hepatic lobules. However, a comprehensive spatiotemporal model of liver regeneration remains elusive, despite recent advancements in genomics, lineage tracing, and microscopic imaging. This review summarizes the spatial distribution of cell gene expression within the regenerative microenvironment and its impact on liver regeneration patterns. It offers valuable insights into understanding the complex process of liver regeneration.

Regeneration refers to the process by which organisms repair and replace lost tissues and organs. Regeneration is widespread in plants and animals; however, the regeneration capabilities of different species vary greatly. Stem cells form the basis for animal and plant regeneration. The essential developmental processes of animals and plants involve totipotent stem cells (fertilized eggs), which develop into pluripotent stem cells and unipotent stem cells. Stem cells and their metabolites are widely used in agriculture, animal husbandry, environmental protection, and regenerative medicine. In this review, we discuss the similarities and differences in animal and plant tissue regeneration, as well as the signaling pathways and key genes involved in the regulation of regeneration, to provide ideas for practical applications in agriculture and human organ regeneration and to expand the application of regeneration technology in the future.