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Biomolecules
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Molecular Mechanisms Underlying Liver Diseases
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Molecular Mechanisms Underlying Liver Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (30 April 2025) | Viewed by 17404

Special Issue Editor

Dr. Wei Zhong

E-Mail Website
Guest Editor
Department of Internal Medicine, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
Interests: alcohol-associated liver disease; gut microbiota; lipid metabolism
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The liver, a central metabolic hub in the human body, plays a pivotal role in maintaining homeostasis and overall health. As an organ of paramount importance, the liver is susceptible to a myriad of diseases, necessitating a comprehensive exploration of the underlying molecular mechanisms. This Special Issue aims to decipher the underlying molecular landscapes governing liver diseases, shedding light on novel insights and potential therapeutic avenues.

This collection of articles aims at addressing a diverse spectrum of liver disorders, encompassing metabolic conditions such as alcohol-associated liver disease and metabolic-associated fatty liver disease, along with viral infections and hepatocellular carcinoma. Our goal is to provide a multifaceted examination of these liver-related pathologies, offering valuable insights into their molecular mechanisms. Furthermore, we recognize the liver not in isolation but as a dynamic organ that engages in constant crosstalk with other physiological systems. Investigating the dynamic interactions between the liver and other organs is integral to our endeavor, as these interactions play a pivotal role in shaping the overall impact of liver diseases on the body. This Special Issue seeks to foster a nuanced understanding of the interplay between molecular factors, genetic determinants, and organ–organ interactions, aiming to contribute meaningfully to the field of hepatic pathophysiology.

In summary, this collection serves as a comprehensive exploration of liver diseases, aiming to unravel the complex tapestry of molecular mechanisms underlying their etiology, progression, and potential therapeutic interventions.

Dr. Wei Zhong
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • pathogenesis of liver diseases
  • molecular mechanisms
  • organelle damages
  • genetic determinants
  • organ–organ interactions
  • biomarkers
  • in vivo models of liver diseases
  • therapeutic insights

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Published Papers (7 papers)

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Research

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17 pages, 3150 KiB  
Article
Single-Cell RNA-Seq Analysis Links DNMT3B and PFKFB4 Transcriptional Profiles with Metastatic Traits in Hepatoblastoma
by Christophe Desterke, Raquel Francés, Claudia Monge, Agnès Marchio, Pascal Pineau and Jorge Mata-Garrido
Biomolecules 2024, 14(11), 1394; https://doi.org/10.3390/biom14111394 - 31 Oct 2024
Cited by 1 | Viewed by 1325
Abstract
Hepatoblastoma is the most common primary liver cancer in children. Poor outcomes are primarily associated with patients who have distant metastases. Using the Mammalian Metabolic Enzyme Database, we investigated the overexpression of metabolic enzymes in hepatoblastoma tumors compared to noncancerous liver tissue in [...] Read more.
Hepatoblastoma is the most common primary liver cancer in children. Poor outcomes are primarily associated with patients who have distant metastases. Using the Mammalian Metabolic Enzyme Database, we investigated the overexpression of metabolic enzymes in hepatoblastoma tumors compared to noncancerous liver tissue in the GSE131329 transcriptome dataset. For the overexpressed enzymes, we applied ElasticNet machine learning to assess their predictive value for metastasis. A metabolic expression score was then computed from the significant enzymes and integrated into a clinical-biological logistic regression model. Forty-one overexpressed enzymes distinguished hepatoblastoma tumors from noncancerous liver tissues. Eighteen of these enzymes predicted metastasis status with an AUC of 0.90, demonstrating 85.7% sensitivity and 92.3% specificity. ElasticNet machine learning identified DNMT3B and PFKFB4 as key predictors of metastasis. Univariate analyses confirmed the significance of these enzymes, with respective p-values of 0.0058 and 0.0091. A metabolic score based on DNMT3B and PFKFB4 expression discriminated metastasis status and high-risk CHIC scores (p-value = 0.005). The metabolic score was more sensitive than the C1/C2 classifier in predicting metastasis (accuracy: 0.72 vs. 0.55). In a regression model integrating the metabolic score with epidemiological parameters (gender, age at diagnosis, histological type, and clinical PRETEXT stage), the metabolic score was confirmed as an independent adverse predictor of metastasis (p-value = 0.003, odds ratio: 2.12). This study identified the dual overexpression of PFKFB4 and DNMT3B in hepatoblastoma patients at risk of metastasis (high-risk CHIC classification). The combined tumor expression of DNMT3B and PFKFB4 was used to compute a metabolic score, which was validated as an independent predictor of metastatic status in hepatoblastoma. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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17 pages, 13879 KiB  
Article
Sirt2 Regulates Liver Metabolism in a Sex-Specific Manner
by Alexandra V. Schmidt, Sivakama S. Bharathi, Keaton J. Solo, Joanna Bons, Jacob P. Rose, Birgit Schilling and Eric S. Goetzman
Biomolecules 2024, 14(9), 1160; https://doi.org/10.3390/biom14091160 - 15 Sep 2024
Cited by 2 | Viewed by 1409
Abstract
Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2−/− males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed [...] Read more.
Sirtuin-2 (Sirt2), an NAD+-dependent lysine deacylase enzyme, has previously been implicated as a regulator of glucose metabolism, but the specific mechanisms remain poorly defined. Here, we observed that Sirt2−/− males, but not females, have decreased body fat, moderate hypoglycemia upon fasting, and perturbed glucose handling during exercise compared to wild type controls. Conversion of injected lactate, pyruvate, and glycerol boluses into glucose via gluconeogenesis was impaired, but only in males. Primary Sirt2−/− male hepatocytes exhibited reduced glycolysis and reduced mitochondrial respiration. RNAseq and proteomics were used to interrogate the mechanisms behind this liver phenotype. Loss of Sirt2 did not lead to transcriptional dysregulation, as very few genes were altered in the transcriptome. In keeping with this, there were also negligible changes to protein abundance. Site-specific quantification of the hepatic acetylome, however, showed that 13% of all detected acetylated peptides were significantly increased in Sirt2−/− male liver versus wild type, representing putative Sirt2 target sites. Strikingly, none of these putative target sites were hyperacetylated in Sirt2−/− female liver. The target sites in the male liver were distributed across mitochondria (44%), cytoplasm (32%), nucleus (8%), and other compartments (16%). Despite the high number of putative mitochondrial Sirt2 targets, Sirt2 antigen was not detected in purified wild type liver mitochondria, suggesting that Sirt2’s regulation of mitochondrial function occurs from outside the organelle. We conclude that Sirt2 regulates hepatic protein acetylation and metabolism in a sex-specific manner. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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14 pages, 4241 KiB  
Article
Peripheral Lymphocytes in Primary Liver Cancers: Elevated NK and CD8+ T Cells and Dysregulated Selenium Metabolism
by Cheng Zhou, Zhufeng Lu, Baoye Sun, Yong Yi, Boheng Zhang, Zheng Wang and Shuang-Jian Qiu
Biomolecules 2024, 14(2), 222; https://doi.org/10.3390/biom14020222 - 14 Feb 2024
Cited by 4 | Viewed by 2733
Abstract
Peripheral blood lymphocytes (PBLs), which play a pivotal role in orchestrating the immune system, garner minimal attention in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The impact of primary liver cancers on PBLs remains unexplored. In this study, flow cytometry facilitated the quantification [...] Read more.
Peripheral blood lymphocytes (PBLs), which play a pivotal role in orchestrating the immune system, garner minimal attention in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). The impact of primary liver cancers on PBLs remains unexplored. In this study, flow cytometry facilitated the quantification of cell populations, while transcriptome of PBLs was executed utilizing 10× single-cell sequencing technology. Additionally, pertinent cases were curated from the GEO database. Subsequent bioinformatics and statistical analyses were conducted utilizing R (4.2.1) software. Elevated counts of NK cells and CD8+ T cells were observed in both ICC and HCC when compared to benign liver disease (BLD). In the multivariate Cox model, NK cells and CD8+ T cells emerged as independent risk factors for recurrence-free survival. Single-cell sequencing of PBLs uncovered the downregulation of TGFβ signaling in tumor-derived CD8+ T cells. Pathway enrichment analysis, based on differential expression profiling, highlighted aberrations in selenium metabolism. Proteomic analysis of preoperative and postoperative peripheral blood samples from patients undergoing tumor resection revealed a significant upregulation of SELENBP1 and a significant downregulation of SEPP1. Primary liver cancer has a definite impact on PBLs, manifested by alterations in cellular quantities and selenoprotein metabolism. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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Review

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14 pages, 2356 KiB  
Review
HBV cccDNA: The Molecular Reservoir of Hepatitis B Persistence and Challenges to Achieve Viral Eradication
by André Boonstra and Gulce Sari
Biomolecules 2025, 15(1), 62; https://doi.org/10.3390/biom15010062 - 4 Jan 2025
Cited by 1 | Viewed by 2320
Abstract
Hepatitis B virus (HBV) is a major global health issue, with an estimated 254 million people living with chronic HBV infection worldwide as of 2022. Chronic HBV infection is the leading cause of cirrhosis and liver cancer. Current treatment with nucleos(t)ide analogs is [...] Read more.
Hepatitis B virus (HBV) is a major global health issue, with an estimated 254 million people living with chronic HBV infection worldwide as of 2022. Chronic HBV infection is the leading cause of cirrhosis and liver cancer. Current treatment with nucleos(t)ide analogs is effective in the suppression of viral activity but generally requires lifelong treatment. They fail to eradicate the HBV viral reservoir, called covalently closed circular DNA (cccDNA), which replicates in the nucleus of liver cells. The cccDNA serves as the sole template for viral replication, as it generates the pregenomic RNA (pgRNA) necessary for producing new viral genomes. This stable form of viral DNA can reactivate the virus when treatment is stopped. HBV cccDNA is therefore one of the main challenges in curing chronic HBV infections. By targeting steps such as cccDNA formation, capsid assembly, or particle secretion, researchers continue to seek ways to interfere with HBV replication and to reduce its persistence, ultimately to eradicate HBV as a global health problem. This review provides an overview of what is currently known about cccDNA formation and biogenesis and the ongoing efforts to target and eradicate it to cure chronic HBV infections. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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24 pages, 837 KiB  
Review
Decoding the Role of O-GlcNAcylation in Hepatocellular Carcinoma
by Xinyu Zhou, Sirui Hang, Qingqing Wang, Liu Xu and Peter Wang
Biomolecules 2024, 14(8), 908; https://doi.org/10.3390/biom14080908 - 25 Jul 2024
Cited by 2 | Viewed by 2381
Abstract
Post-translational modifications (PTMs) influence protein functionality by modulating protein stability, localization, and interactions with other molecules, thereby controlling various cellular processes. Common PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, SUMOylation, methylation, sulfation, and nitrosylation. Among these modifications, O-GlcNAcylation has been shown to play a [...] Read more.
Post-translational modifications (PTMs) influence protein functionality by modulating protein stability, localization, and interactions with other molecules, thereby controlling various cellular processes. Common PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, SUMOylation, methylation, sulfation, and nitrosylation. Among these modifications, O-GlcNAcylation has been shown to play a critical role in cancer development and progression, especially in hepatocellular carcinoma (HCC). This review outlines the role of O-GlcNAcylation in the development and progression of HCC. Moreover, we delve into the underlying mechanisms of O-GlcNAcylation in HCC and highlight compounds that target O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) to improve treatment outcomes. Understanding the role of O-GlcNAcylation in HCC will offer insights into potential therapeutic strategies targeting OGT and OGA, which could improve treatment for patients with HCC. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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30 pages, 2551 KiB  
Review
Macrophage Perspectives in Liver Diseases: Programmed Death, Related Biomarkers, and Targeted Therapy
by Zibing Qian, Wanyuan Xiong, Xiaorong Mao and Junfeng Li
Biomolecules 2024, 14(6), 700; https://doi.org/10.3390/biom14060700 - 14 Jun 2024
Cited by 2 | Viewed by 2277
Abstract
Macrophages, as important immune cells of the organism, are involved in maintaining intrahepatic microenvironmental homeostasis and can undergo rapid phenotypic changes in the injured or recovering liver. In recent years, the crucial role of macrophage-programmed cell death in the development and regression of [...] Read more.
Macrophages, as important immune cells of the organism, are involved in maintaining intrahepatic microenvironmental homeostasis and can undergo rapid phenotypic changes in the injured or recovering liver. In recent years, the crucial role of macrophage-programmed cell death in the development and regression of liver diseases has become a research hotspot. Moreover, macrophage-targeted therapeutic strategies are emerging in both preclinical and clinical studies. Given the macrophages’ vital role in complex organismal environments, there is tremendous academic interest in developing novel therapeutic strategies that target these cells. This review provides an overview of the characteristics and interactions between macrophage polarization, programmed cell death, related biomarkers, and macrophage-targeted therapies. It aims to deepen the understanding of macrophage immunomodulation and molecular mechanisms and to provide a basis for the treatment of macrophage-associated liver diseases. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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34 pages, 4303 KiB  
Review
Molecular Mechanisms in Tumorigenesis of Hepatocellular Carcinoma and in Target Treatments—An Overview
by Raluca-Margit Szilveszter, Mara Muntean and Adrian Florea
Biomolecules 2024, 14(6), 656; https://doi.org/10.3390/biom14060656 - 4 Jun 2024
Cited by 4 | Viewed by 3672
Abstract
Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection [...] Read more.
Hepatocellular carcinoma is the most common primary malignancy of the liver, with hepatocellular differentiation. It is ranked sixth among the most common cancers worldwide and is the third leading cause of cancer-related deaths. The most important etiological factors discussed here are viral infection (HBV, HCV), exposure to aflatoxin B1, metabolic syndrome, and obesity (as an independent factor). Directly or indirectly, they induce chromosomal aberrations, mutations, and epigenetic changes in specific genes involved in intracellular signaling pathways, responsible for synthesis of growth factors, cell proliferation, differentiation, survival, the metastasis process (including the epithelial–mesenchymal transition and the expression of adhesion molecules), and angiogenesis. All these disrupted molecular mechanisms contribute to hepatocarcinogenesis. Furthermore, equally important is the interaction between tumor cells and the components of the tumor microenvironment: inflammatory cells and macrophages—predominantly with a pro-tumoral role—hepatic stellate cells, tumor-associated fibroblasts, cancer stem cells, extracellular vesicles, and the extracellular matrix. In this paper, we reviewed the molecular biology of hepatocellular carcinoma and the intricate mechanisms involved in hepatocarcinogenesis, and we highlighted how certain signaling pathways can be pharmacologically influenced at various levels with specific molecules. Additionally, we mentioned several examples of recent clinical trials and briefly described the current treatment protocol according to the NCCN guidelines. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Liver Diseases)
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