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.

Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.

Liver regeneration (LR) is a unique biological process with the ability to restore up to 70% of the organ. This allows for the preservation of liver resections for various liver tumors and for living donor liver transplantation (LDLT). However, in some cases, LR is insufficient and interventions that can improve LR are urgently needed. Gut microbiota (GM) is one of the factors influencing LR, as the liver and intestine are intimately connected through the gut-liver axis. Thus, healthy GM facilitates normal LR, whereas dysbiosis leads to impaired LR due to imbalance of bile acids, inflammatory cytokines, microbial metabolites, signaling pathways, etc. Therefore, GM can be considered as a new possible therapeutic target to improve LR. In this review, we critically observe the current knowledge about the influence of gut microbiota (GM) on liver regeneration (LR) and the possibility to improve this process, which may reduce complication and mortality rates after liver surgery. Although much research has been done on this topic, more clinical trials and systemic reviews are urgently needed to move this type of intervention from the experimental phase to the clinical field.

Surgical resection is a pivotal therapeutic approach for addressing hepatic space-occupying lesions, with liver volume restoration and hepatic functional recovery being crucial for assessing surgical prognosis. The preoperative albumin-bilirubin (ALBI) score, encompassing serum albumin and bilirubin levels, can be determined via blood analysis, effectively mitigating human error and providing an accurate depiction of liver function. The hepatectomy ratio, which is the proportion of the liver volume removed to the total liver volume, is critical in preserving an adequate liver tissue volume to ensure postoperative hepatic functional compensation, minimize surgical complications, and reduce mortality rates. Incorporating the preoperative ALBI score and hepatectomy ratio aids surgeons in assessing the optimal timing and extent of partial hepatectomy. The introduction of preoperative albumin bilirubin score and hepatectomy percentage is beneficial for the surgeons to evaluate the timing and magnitude of partial liver resection.

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a severe rare liver disease that affects between 1/50,000 and 1/100,000 children. In physiological conditions, bile is produced by the liver and stored in the gallbladder, and then it flows to the small intestine to play its role in fat digestion. To prevent tissue damage, bile acids (BAs) are kept in phospholipid micelles. Mutations in phosphatidyl choline transporter ABCB4 (MDR3) lead to intrahepatic accumulation of free BAs that result in liver damage. PFIC3 onset usually occurs at early ages, progresses rapidly, and the prognosis is poor. Currently, besides the palliative use of ursodeoxycholate, the only available treatment for this disease is liver transplantation, which is really challenging for short-aged patients. To gain insight into the pathogenesis of PFIC3 we have performed an integrated proteomics and phosphoproteomics study in human liver samples to then validate the emerging functional hypotheses in a PFIC3 murine model. We identified 6246 protein groups, 324 proteins among them showing differential expression between control and PFIC3. The phosphoproteomic analysis allowed the identification of 5090 phosphopeptides, from which 215 corresponding to 157 protein groups, were differentially phosphorylated in PFIC3, including MDR3. Regulation of essential cellular processes and structures, such as inflammation, metabolic reprogramming, cytoskeleton and extracellular matrix remodeling, and cell proliferation, were identified as the main drivers of the disease. Our results provide a strong molecular background that significantly contributes to a better understanding of PFIC3 and provides new concepts that might prove useful in the clinical management of patients.

Cluster of differentiation 44 (CD44), a multi-functional cell surface receptor, has several variants and is ubiquitously expressed in various cells and tissues. CD44 is well known for its function in cell adhesion and is also involved in diverse cellular responses, such as proliferation, migration, differentiation, and activation. To date, CD44 has been extensively studied in the field of cancer biology and has been proposed as a marker for cancer stem cells. Recently, growing evidence suggests that CD44 is also relevant in non-cancer diseases. In liver disease, it has been shown that CD44 expression is significantly elevated and associated with pathogenesis by impacting cellular responses, such as metabolism, proliferation, differentiation, and activation, in different cells. However, the mechanisms underlying CD44's function in liver diseases other than liver cancer are still poorly understood. Hence, to help to expand our knowledge of the role of CD44 in liver disease and highlight the need for further research, this review provides evidence of CD44's effects on liver physiology and its involvement in the pathogenesis of liver disease, excluding cancer. In addition, we discuss the potential role of CD44 as a key regulator of cell physiology.

Diabetes is not a single disease but rather, it is one aspect of metabolic syndrome. The pathologic aspects of diabetes involve cellular changes that need to be understood.

The main objective of this study was to explore the role of Ki67 in the liver of diabetic rats.

The study methodology involved the induction of diabetes in rats using Alloxan (120 mg/kg). A total of 20 albino rats were randomly assigned into two groups control group (N=10) and diabetes group (n=10). Diabetic group received the dose of alloxan, while the control group received similar dose of normal saline. Glucose level was monitored daily. After the end of the experiment (one -month period), all animals were terminated. Blood samples were taken to measure biochemical investigations including glucose, cholesterol, and triglycerides. Liver tissue was excised and washed with normal saline and fixed in buffered formalin (10%). Liver tissue was processed and stained by hematoxylin and eosin for routine histological examination and also stained by immunohistochemistry for Ki67 biomarker.

The results revealed the efficacy of the diabetic model. All biochemical investigations were significantly higher in the diabetic group compared with that of control group (p<0.001). Histological studies showed the existence of morphological alterations in cells and fatty changes in the diabetic group compared with the control group. The expression of Ki67 was significantly higher in the diabetic group compared with that in the control group (p=0.011).

Taken together, diabetes has adverse effects on the spleen from a histological point of view, and from the expression of Ki67.

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.

Since the first discovery of microRNAs (miRs) extensive evidence reveals their indispensable role in different patho-physiological processes. They are recognized as critical regulators of hepatic regeneration, as they modulate multiple complex signaling pathways affecting liver regeneration. MiR-related translational suppression and degradation of target mRNAs and proteins are not limited to one specific gene, but act on multiple targets.

In this review, we are going to explore the role of miRs in the context of liver regeneration and discuss the regulatory effects attributed to specific miRs. Moreover, specific pathways crucial for liver regeneration will be discussed, with a particular emphasis on the involvement of miRs within the respective signaling cascades.

The considerable amount of studies exploring miR functions in a variety of diseases paved the way for the development of miR-directed therapeutics. Clinical implementation has already shown promising results, but additional research is warranted to assure safe and efficient delivery. Nevertheless, given the broad functional properties of miRs and their critical involvement during hepatic regeneration, they represent an attractive treatment target to promote liver recovery after hepatic resection.

Partial hepatectomy (PH) can lead to severe complications, including liver failure, due to the low regenerative capacity of the remaining liver, especially after extensive hepatectomy. Liver sinusoidal endothelial cells (LSECs), whose proliferation occurs more slowly and later than hepatocytes after PH, compose the lining of the hepatic sinusoids, which are the smallest blood vessels in the liver. Vascular endothelial growth factor (VEGF), secreted by hepatocytes, promotes LSEC proliferation. Supplementation of exogenous VEGF after hepatectomy also increases the number of LSECs in the remaining liver, thus promoting the reestablishment of the hepatic sinusoids and accelerating liver regeneration. At present, some shortcomings exist in the methods of supplementing exogenous VEGF, such as a low drug concentration in the liver and the reaching of other organs. More-over, VEGF should be administered multiple times and in large doses because of its short half-life. This review summarized the most recent findings on liver regeneration and new strategies for the localized delivery VEGF in the liver.