Spatial hepatology: Decoding liver zonation for metabolic and regenerative therapeutics (Review)

Deciphering the Cell-Specific Role of Wnts in the Liver: New Tools for a Difficult Task.

Liver disease is a major global health-care problem, affecting an estimated 844 million people worldwide. Despite this substantial burden, therapeutic options for liver disease remain limited, in part owing to a paucity of detailed analyses defining the cellular and molecular mechanisms that drive these conditions in humans. Single-cell transcriptomic technologies are transforming our understanding of cellular diversity and function in health and disease. In this Review, we discuss how these technologies have been applied in hepatology, advancing our understanding of cellular heterogeneity and providing novel insights into fundamental liver biology such as the metabolic zonation of hepatocytes, endothelial cells and hepatic stellate cells, and the cellular mechanisms underpinning liver regeneration. Application of these methodologies is also uncovering critical pathophysiological changes driving disease states such as hepatic fibrosis, where distinct populations of macrophages, endothelial cells and mesenchymal cells reside within a spatially distinct fibrotic niche and interact to promote scar formation. In addition, single-cell approaches are starting to dissect key cellular and molecular functions in liver cancer. In the near future, new techniques such as spatial transcriptomics and multiomic approaches will further deepen our understanding of disease pathogenesis, enabling the identification of novel therapeutic targets for patients across the spectrum of liver diseases.

Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

S-adenosylmethionine (SAMe) therapy in liver disease: A review of current evidence and clinical utility

The evidence-based multifaceted roles of hepatic stellate cells in liver diseases: A concise review

The present review comprehensively discusses the impact of circadian clock genes on hepatic metabolism, liver disease progression and therapeutic strategies. The circadian rhythm, as a fundamental regulatory system, governs metabolic, immune and endocrine processes through an integrated central‑peripheral network. Disruption of this rhythm plays a pivotal role in the pathogenesis of various liver diseases, including non‑alcoholic fatty liver disease, alcoholic liver disease, liver fibrosis and hepatocellular carcinoma. Key circadian regulators, including circadian locomotor output cycles kaput, brain and muscle ARNT‑like protein 1, period circadian regulator 1/2 and cryptochrome 1/2 modulate critical pathways, including lipid and glucose metabolism, bile acid synthesis, inflammatory responses and cellular repair, thereby contributing to the progression of liver disease. Chronotherapeutic approaches, such as targeted pharmacological treatments, time‑restricted feeding and light therapy, show promising clinical potential. However, further research is essential to clarify the underlying mechanisms and enable clinical application. By integrating foundational studies with clinical evidence, the present review provides a framework for chrono‑precision medicine in hepatology, while identifying current challenges and proposing strategies to accelerate the development and clinical implementation of circadian rhythm‑based therapies for liver disease.

Nonalcoholic fatty liver disease (NAFLD), the major reason for abnormal liver function in the Western world, is associated with obesity and diabetes and is characterized by insulin resistance (IR). IR is regulated by mediators released from cells of the immune system or adipocytes and proinflammatory cytokines such as tumor necrosis factor-α (TNFα). The importance of TNFα in human and animal fatty liver diseases, both caused by genetic manipulation and overnutrition, has been shown convincingly. Furthermore, neutralization of TNFα activity improves IR and fatty liver disease in animals. Adiponectin is a potent TNFα-neutralizing and anti-inflammatory adipokine and in vitro and experimental animal studies have proven the importance of this mediator in counteracting inflammation and IR. Anti-inflammatory effects of adiponectin are exerted both by suppressing TNFα synthesis and by induction of anti-inflammatory cytokines such as interleukin-10 or interleukin-1–receptor antagonist. Therefore, the balance between various mediators, either derived from the immune system or adipose tissue, appears to play an important role in hepatic and systemic insulin action and in the development of fatty liver disease.

Histone acetyltransferases are responsible for histone acetylation, while histone deacetylases (HDACs) counteract histone acetylation. An unbalanced dynamic between histone acetylation and deacetylation may lead to aberrant chromatin landscape and chromosomal function. HDAC2, a member of class I HDAC family, serves a crucial role in the modulation of cell signaling, immune response and gene expression. HDAC2 has emerged as a promising therapeutic target for liver disease by regulating gene transcription, chromatin remodeling, signal transduction and nuclear reprogramming, thus receiving attention from researchers and clinicians. The present review introduces biological information of HDAC2 and its physiological and biochemical functions. Secondly, the functional roles of HDAC2 in liver disease are discussed in terms of hepatocyte apoptosis and proliferation, liver regeneration, hepatocellular carcinoma, liver fibrosis and non-alcoholic steatohepatitis. Moreover, abnormal expression of HDAC2 may be involved in the pathogenesis of liver disease, and its expression levels and pharmacological activity may represent potential biomarkers of liver disease. Finally, research on selective HDAC2 inhibitors and non-coding RNAs relevant to HDAC2 expression in liver disease is also reviewed. The aim of the present review was to improve understanding of the multifunctional role and potential regulatory mechanism of HDAC2 in liver disease.

Roles for Chemokines in Liver Disease

Environmental factors as disease accelerators during chronic hepatitis C

Excessive alcohol consumption contributes to a broad clinical spectrum of liver diseases, from simple steatosis to end-stage hepatocellular carcinoma. The liver is the primary organ that metabolizes ingested alcohol and is exquisitely sensitive to alcohol intake. Alcohol metabolism is classified into two pathways: oxidative and non-oxidative alcohol metabolism. Both oxidative and non-oxidative alcohol metabolisms and their metabolites have toxic consequences for multiple organs, including the liver, adipose tissue, intestine, and pancreas. Although many studies have focused on the effects of oxidative alcohol metabolites on liver damage, the importance of non-oxidative alcohol metabolites in cellular damage has also been discovered. Furthermore, extrahepatic alcohol effects are crucial for providing additional information necessary for the progression of alcoholic liver disease. Therefore, studying the effects of alcohol-producing metabolites and interorgan crosstalk between the liver and peripheral organs that express ethanol-metabolizing enzymes will facilitate a comprehensive understanding of the pathogenesis of alcoholic liver disease. This review focuses on alcohol-metabolite-associated hepatotoxicity due to oxidative and non-oxidative alcohol metabolites and the role of interorgan crosstalk in alcoholic liver disease pathogenesis.

Chronic liver disease including non-alcoholic fatty liver disease and alcohol-related liver disease is one of the most common diseases worldwide. The gut-liver axis plays an important role in the pathogenesis of liver disease. Small intestinal bacterial overgrowth, dysbiosis, leaky bowel, bacterial translocation, and imbalanced metabolites are related to the progression of chronic liver disease. Recently, novel therapeutic approaches for microbiota modulation such as personalized diet, probiotics, prebiotics, antibiotics, engineered microbiotas, phage therapy, stomach operation, and fecal microbiota transplantation (FMT) have been proposed with numerous promising results in the effectiveness and clinical application. Although the evidence is still lacking, FMT, a type of fecal bacteriotherapy, has been known as a candidate for the treatment of liver disease. This review article focuses on the most recent advances in our understanding of FMT in chronic liver disease such as non-alcoholic and alcohol-related liver disease.

Lipids in Liver Disease: Looking Beyond Steatosis

Circular RNAs (circRNAs) are a subclass of noncoding RNAs characterized by their closed-loop structure without terminal 3' or 5' ends. Studies have shown that circRNAs play pivotal roles in the regulation of various cellular processes. These molecules function as microRNA (miRNA) sponges, interact with RNA-binding proteins, and modulate gene transcription. CircRNAs are vital for regulating liver homeostasis, and dysregulation of their expression is correlated with liver diseases such as hepatic fibrosis, steatosis, inflammation, and liver cancer. Elucidating the functional significance of circRNAs in liver diseases is crucial, as this knowledge may facilitate the identification of novel diagnostic biomarkers and therapeutic targets for conditions that contribute significantly to global morbidity and mortality. This review aimed to highlight current research underscoring the functional roles of circRNAs in the molecular pathogenesis and progression of liver diseases, including hepatocellular carcinoma, nonalcoholic fatty liver disease, and liver fibrosis. To provide an updated and comprehensive overview, a literature search was conducted across major scientific databases. This review reveals that circRNAs perform multifaceted functions in liver homeostasis and disease by regulating gene expression through miRNA sponging, interacting with signaling pathways, and influencing cellular processes, including vascularization, metastasis, the cell cycle, apoptosis, cellular stress, metabolic activity, inflammatory responses, and cellular senescence. Despite their pivotal involvement in liver diseases, translating circRNA-based research into clinical practice remains challenging. In conclusion, circRNAs represent an emerging frontier in liver disease research, offering considerable promise for future clinical applications.

Matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play critical roles in the pathogenesis of liver diseases, particularly in conditions such as fibrosis, cirrhosis, and liver cancer. This review highlights the diagnostic and prognostic potential of MMPs, emphasizing their involvement in metastasis, de-differentiation, and hepatic cell proliferation. Utilizing advanced reporter mouse models has proven instrumental in assessing intraglandular MMP activity and predicting metastatic risks, paving the way for targeted therapeutic interventions. Current research indicates that specific MMPs and TIMPs can serve as valuable biomarkers for liver function and disease progression, although a clear consensus on their clinical utility remains elusive. Ongoing studies explore MMP-targeted therapies with potential applications in liver disease management, particularly in reducing fibrosis and enhancing liver regeneration. Future directions in this field involve elucidating the roles of MMPs in ischemia and transplantation, with the aim of improving clinical outcomes. Emerging therapeutic strategies focus on achieving a balance between MMP activity and TIMP expression to optimize liver function, highlighting the need for organ-specific targeting. Overall, this comprehensive overview underscores the importance of MMPs and TIMPs in liver function and liver disease, as well as the necessity for further research to harness their potential in clinical practice.