Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
10.0
5.6
Journals
IJMS
Special Issues
Molecular Insights into Chronic Liver Disease and Liver Failure
ijms-logo
Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

► Journal Menu

Journal Browser

► Journal Browser
share announcement

Molecular Insights into Chronic Liver Disease and Liver Failure

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 June 2026) | Viewed by 6480

Editor

Dr. Paolo Gallo

E-Mail Website
Guest Editor
Operative Research Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy
Interests: cirrhosis; sarcopenia; malnutrition; portal hypertension; ultrasound

Special Issue Information

Dear Colleagues,

Chronic liver disease represents a significant global health burden, affecting millions of people and leading to significant morbidity and mortality. The concept of chronic liver failure encompasses a wide range of underlying conditions and clinical manifestations, reflecting the complex and multifaceted nature of liver disease progression.

A comprehensive understanding of the pathophysiology of chronic liver disease is essential to advance diagnostic, clinical, and therapeutic approaches. Recent research has provided new insights into disease mechanisms, enabling the development of more accurate diagnostic tools and targeted treatments. In addition, practical clinical methods are essential for the effective management of chronic liver disease in daily practice, providing clinicians with valuable strategies for patient care.

This Special Issue invites contributions that address advances in the study of chronic liver disease, covering topics such as pathophysiological insights, innovative diagnostic techniques, clinical management, and therapeutic approaches.

Dr. Paolo Gallo
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 250 words) can be sent to the Editorial Office for assessment.

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-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • cirrhosis
  • portal hypertension
  • liver failure
  • advanced chronic liver disease
  • sarcopenia and malnutrition
  • ascites
  • medical treatment

Benefits of Publishing in a Special Issue

  • Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
  • Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
  • Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
  • External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
  • Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (7 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review, Other

29 pages, 18861 KB  
Article
Experimental Models of Metabolic Dysfunction-Associated Steatotic Liver Disease: A Comparative Analysis of a Choline-Deficient and Cholesterol-Enriched Diet in Rats
by Vladimir A. Shipelin, Nikita A. Petrov, Nikita V. Trusov, Yuliya S. Sidorova, Yulia M. Markova, Zakhar A. Chalyy, Anton D. Konev and Anastasiya S. Balakina
Int. J. Mol. Sci. 2026, 27(10), 4230; https://doi.org/10.3390/ijms27104230 - 9 May 2026
Viewed by 538
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread pathology requiring adequate preclinical models for studying pathogenesis and evaluating therapeutic and preventive agents. This study compared differential markers of MASLD pathogenesis in rats using two distinct dietary models: a choline-deficient high-fat diet (HFD-CD) [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread pathology requiring adequate preclinical models for studying pathogenesis and evaluating therapeutic and preventive agents. This study compared differential markers of MASLD pathogenesis in rats using two distinct dietary models: a choline-deficient high-fat diet (HFD-CD) and a cholesterol-enriched high-fat diet (HFD+CHOL). Male Wistar rats were fed either a control AIN93M diet, HFD-CD (40% fat, 20% fructose, and choline deficiency), or HFD+CHOL (40% fat, 20% fructose, and 1% cholesterol) for 56 days. Comprehensive assessment included phenotypic, biochemical, hematological, histomorphological parameters, oxidative stress markers, hepatocyte apoptosis, cytokine levels, and hepatic gene expression. HFD-CD induced steatosis with moderate insulin resistance, increased malondialdehyde levels, and suppressed Acaca, Scd and ChREBP gene expression. In contrast, HFD+CHOL caused macrovesicular steatosis, inflammation, early fibrosis, atherogenic dyslipidemia, intrahepatic cholesterol accumulation, hepatocyte apoptosis, upregulated Srebf1, Cyp7a1, and Nfkb1 expression, and activated Nrf2-dependent antioxidant responses. HFD-CD and HFD+CHOL induce two pathogenetically distinct MASLD phenotypes. The HFD-CD model, characterized by steatosis and oxidative stress without pronounced inflammation or fibrosis, is preferable for studying the preventive potential of bioactive food compounds. Conversely, the HFD+CHOL model with inflammatory and fibrotic components is more suitable for evaluating therapeutic agents aimed at mitigating inflammation, restoring cholesterol homeostasis, and attenuating fibrosis. Full article
(This article belongs to the Special Issue Molecular Insights into Chronic Liver Disease and Liver Failure)
►▼ Show Figures

Graphical abstract

18 pages, 2475 KB  
Article
Reproducibility and Sex Differences in a STZ–High-Fat Diet Model of MASLD and Early Hepatocarcinogenesis
by Marleigh Hefner, Raksa Andalib Hia, Tiffany Nguyen, Masoud Nateqi, Nikhil V. Dhurandhar and Vijay Hegde
Int. J. Mol. Sci. 2026, 27(7), 3200; https://doi.org/10.3390/ijms27073200 - 1 Apr 2026
Viewed by 1065
Abstract
Primary liver cancer, particularly hepatocellular carcinoma (HCC), remains a major global health burden, ranking as the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. The rising incidence of HCC is closely linked to metabolic comorbidities, including non-alcoholic fatty [...] Read more.
Primary liver cancer, particularly hepatocellular carcinoma (HCC), remains a major global health burden, ranking as the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. The rising incidence of HCC is closely linked to metabolic comorbidities, including non-alcoholic fatty liver disease (NAFLD), underscoring the need for improved diagnostic and therapeutic strategies. NAFLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), characterized by inflammation and fibrosis, which markedly increases HCC risk, especially in individuals with obesity and type 2 diabetes (T2D). NAFLD has recently been redefined as metabolic dysfunction-associated steatotic liver disease (MASLD) to better reflect its metabolic basis. However, robust experimental models to study the progression from MASLD to MASH and ultimately HCC remain limited. This proof-of-concept study investigates sex-specific effects of metabolic dysregulation using the STAM (STelic Animal Model; streptozotocin and high-fat diet) mouse model, which recapitulates key features of human MASH and HCC. Neonatal C57BL/6J mice received streptozotocin to induce T2D-like symptoms followed by a high-fat diet. Streptozotocin (STZ) treated mice showed reduced body fat, lower insulin levels, impaired glucose tolerance, and increased expression of genes linked to inflammation, lipid metabolism, and apoptosis. These findings support the STAM model’s utility for MASLD research and highlight the importance of sex-specific strategies to limit HCC progression. Full article
(This article belongs to the Special Issue Molecular Insights into Chronic Liver Disease and Liver Failure)
►▼ Show Figures

Figure 1

11 pages, 652 KB  
Article
Soluble CD14 Levels Predict Liver Fibrosis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Independently of Obesity and Type 2 Diabetes
by Ilaria Barchetta, Flavia Agata Cimini, Federica Sentinelli, Sara Dule, Valentina Frattina, Giulia Passarella, Maria Neve Hirsch, Alessandro Oldani, Marco Giorgio Baroni and Maria Gisella Cavallo
Int. J. Mol. Sci. 2026, 27(7), 3050; https://doi.org/10.3390/ijms27073050 - 27 Mar 2026
Viewed by 681
Abstract
Increased intestinal permeability has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), but its relationship with liver fibrosis independent of metabolic risk factors remains unclear. The aim of this study was to investigate the relationship between markers of gut-derived immune activation and [...] Read more.
Increased intestinal permeability has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD), but its relationship with liver fibrosis independent of metabolic risk factors remains unclear. The aim of this study was to investigate the relationship between markers of gut-derived immune activation and liver fibrosis in individuals with metabolic disease. We enrolled 139 adults (48.8 ± 11 years; BMI 33.7 ± 9.5 kg/m2; 50% type 2 diabetes); liver steatosis and fibrosis were estimated using the Hepatic Steatosis Index (HSI) and Fibrotic NASH Index (FNI); liver biopsies were available in a bariatric subgroup. Plasma soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) levels were measured by ELISA kits, and the LBP/sCD14 ratio was calculated. MASLD was present in 78% of participants; in these individuals, sCD14 levels correlated with HSI and FNI (both p < 0.01). In multivariable analysis adjusting for age, sex, BMI, waist circumference, and type 2 diabetes, sCD14 was independently associated with advanced fibrosis (OR: 3.16, 95% CI 1.32–7.55; p = 0.010). This association was confirmed by histology (p = 0.02). Overall, these findings point to a link between gut-derived immune activation and fibrotic burden in MASLD and provide insight into the pathophysiological relevance of the gut–liver axis in metabolic disease. Full article
(This article belongs to the Special Issue Molecular Insights into Chronic Liver Disease and Liver Failure)
►▼ Show Figures

Figure 1

Review

Jump to: Research, Other

15 pages, 1228 KB  
Review
Hepassocin (FGL-1) as a Hepatokine in Liver Physiology and Metabolic Dysfunction: A Narrative Review
by Hung-Chih Chen, Hiong-Ping Hii, Kai-Pi Cheng, Hung-Tsung Wu, Hsin-Yu Kuo and Horng-Yih Ou
Int. J. Mol. Sci. 2026, 27(13), 5699; https://doi.org/10.3390/ijms27135699 - 24 Jun 2026
Viewed by 99
Abstract
Hepassocin, also known as fibrinogen-like protein 1 (FGL-1), is a liver-derived secretory protein initially identified as a mitogenic factor involved in hepatocyte proliferation and liver regeneration. Increasing evidence has subsequently suggested that FGL-1 functions as a hepatokine linking hepatic metabolic stress to systemic [...] Read more.
Hepassocin, also known as fibrinogen-like protein 1 (FGL-1), is a liver-derived secretory protein initially identified as a mitogenic factor involved in hepatocyte proliferation and liver regeneration. Increasing evidence has subsequently suggested that FGL-1 functions as a hepatokine linking hepatic metabolic stress to systemic metabolic regulation. Experimental and clinical studies have demonstrated that circulating FGL-1 levels are associated with obesity, insulin resistance, metabolic dysfunction-associated steatotic liver disease (MASLD), and type 2 diabetes mellitus (T2DM). Mechanistically, FGL-1 appears to contribute to metabolic dysfunction by impairing insulin signaling and promoting hepatic lipid accumulation, although its precise molecular targets remain incompletely defined. In addition to its metabolic roles, FGL-1 has been identified as a major ligand of lymphocyte activation gene-3 (LAG-3), implicating it in immune modulation and tumor progression, particularly in hepatocellular carcinoma (HCC). However, most available human data are observational, and conflicting findings from experimental models suggest that FGL-1 may function as a context-dependent mediator rather than a purely pathogenic factor. Given the expanding but sometimes conflicting evidence, a comprehensive understanding of FGL-1 biology may provide important insights into the complex interactions among hepatic stress responses, metabolic dysfunction, and immune regulation. This review therefore examines the current evidence regarding the physiological and pathological roles of FGL-1 and highlights key unresolved questions that may influence future translational research and therapeutic development. Full article
(This article belongs to the Special Issue Molecular Insights into Chronic Liver Disease and Liver Failure)
►▼ Show Figures

Figure 1

36 pages, 6022 KB  
Review
Hepatocyte Models for Metabolic Dysfunction-Associated Steatotic Liver Disease: A Comparative Analysis of Non-HepG2 Cell Models
by Anna Kotlyarova and Stanislav Kotlyarov
Int. J. Mol. Sci. 2026, 27(10), 4453; https://doi.org/10.3390/ijms27104453 - 15 May 2026
Viewed by 770
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread condition with a complex pathogenesis. Cell-based models are important tools for studying the mechanisms underlying its development and progression. The aim of this review is to analyze the HepaRG, Huh-7, immortalized human hepatocyte (IHH), [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread condition with a complex pathogenesis. Cell-based models are important tools for studying the mechanisms underlying its development and progression. The aim of this review is to analyze the HepaRG, Huh-7, immortalized human hepatocyte (IHH), and primary human hepatocyte (PHH) cell lines for modeling and studying MASLD. HepaRG represents the most metabolically competent immortalized hepatocyte model with preserved biotransformation activity and a physiological bioenergetic response to lipid loading, making it valuable for pharmacological and toxicological studies. Huh-7 is distinguished by its accessibility and suitability for studying steatosis, lipotoxicity, insulin resistance, and paracrine mechanisms of fibrogenesis; however, its use is limited by its tumor origin, impaired carbohydrate metabolism, and low activity of xenobiotic-metabolizing enzymes. The IHH model occupies an intermediate position because of its non-tumor origin and is of interest for studies of senescence, epigenetic regulation, and signaling pathways involved in steatosis, although interpretation of results requires consideration of immortalization-related effects and specific metabolic limitations. PHH remains the most physiologically relevant platform for MASLD modeling, particularly in three-dimensional (3D) and microphysiological formats; however, its use is limited by high cost, interindividual variability, and the limited duration of the differentiated phenotype. Increasing model complexity—from two-dimensional (2D) monocultures to co-cultures, spheroids, and organ-on-chip systems—enhances physiological relevance and enables reproduction not only of steatosis but also of the inflammatory and fibrogenic components of MASLD progression, yet it reduces reproducibility and complicates standardization. Overall, none of the existing models is universal, and the optimal strategy is to select models according to the specific research question. A key direction for future research is the standardization of steatosis induction protocols and the unification of criteria for evaluating results. Full article
(This article belongs to the Special Issue Molecular Insights into Chronic Liver Disease and Liver Failure)
►▼ Show Figures

Figure 1

27 pages, 1243 KB  
Review
The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease
by Anna Kotlyarova, Aleksandra Iskrina and Stanislav Kotlyarov
Int. J. Mol. Sci. 2026, 27(8), 3399; https://doi.org/10.3390/ijms27083399 - 10 Apr 2026
Cited by 1 | Viewed by 2462
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in the world. The disease progresses from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The modern concept of [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in the world. The disease progresses from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The modern concept of “multiple parallel hits” interprets disease progression as the result of the synergistic action of lipotoxicity, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, proinflammatory signals, and gut–liver axis dysfunction. Against the background of the limited translation of preclinical data from animal models due to interspecies differences, the importance of human-oriented in vitro platforms compatible with controlled design and high-throughput screening is increasing. The current review analyzes MASLD models based on the HepG2 cell line, systematizing steatosis induction protocols, evaluating the metabolic characteristics and limitations of this cell, and comparing 2D monocultures, 3D systems, and co-cultures. HepG2 has been shown to demonstrate a predictable steatogenic response to free fatty acids (FFAs) and is convenient for reproducing early stages of pathogenesis and primary pharmacological selection of compounds. At the same time, key limitations of the model are highlighted, namely tumor origin, glycolytic shift (Warburg effect), reduced β-oxidation, impaired very-low-density lipoprotein (VLDL) assembly and secretion, and sharply reduced cytochrome P450 (CYP450) activity, as well as limited reproducibility of fructose-induced de novo lipogenesis (DNL). Comparative analysis demonstrates an increase in physiological relevance with the transition from 2D to 3D and multicomponent co-cultures, accompanied by increased complexity and cost, but allowing for the modeling of inflammation and fibrogenesis. The review justifies approaches to selecting the appropriate platform based on the specific research task. Full article
(This article belongs to the Special Issue Molecular Insights into Chronic Liver Disease and Liver Failure)
►▼ Show Figures

Figure 1

Other

Jump to: Research, Review

5 pages, 457 KB  
Case Report
Hepatic Alpha-1 Antitrypsin Globules in Compound Heterozygous SERPINA1 Variants Previously Considered Non-Polymerizing: A Case Report
by Panaiotis Finamore, Simona Santangelo, Paolo Gallo, Ilaria Ferrarotti, Alice Maria Balderacchi, Andrea Falcomatà, Daniele Colombo, Franca Del Nonno, Umberto Vespasiani-Gentilucci, Raffaele Antonelli Incalzi and Simone Scarlata
Int. J. Mol. Sci. 2026, 27(12), 5589; https://doi.org/10.3390/ijms27125589 - 20 Jun 2026
Viewed by 131
Abstract
Alpha-1 antitrypsin deficiency (AATD) is a genetically heterogeneous disorder with well-established pulmonary and hepatic manifestations; however, the clinical significance of rare compound heterozygous SERPINA1 variants remains incompletely defined. We report the case of a 61-year-old never-smoking woman with chronically elevated liver transaminase who [...] Read more.
Alpha-1 antitrypsin deficiency (AATD) is a genetically heterogeneous disorder with well-established pulmonary and hepatic manifestations; however, the clinical significance of rare compound heterozygous SERPINA1 variants remains incompletely defined. We report the case of a 61-year-old never-smoking woman with chronically elevated liver transaminase who was found to carry a compound heterozygous SERPINA1 genotype (PI*V/Mprocida) previously classified as non-polymerogenic and not previously associated with hepatic inclusions. This case expands the phenotypic spectrum of AATD and highlights the importance of considering SERPINA1 genotyping in adults with unexplained chronic transaminase elevation, while raising clinically relevant questions regarding surveillance and management in atypical AATD phenotypes. Full article
(This article belongs to the Special Issue Molecular Insights into Chronic Liver Disease and Liver Failure)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-7
Back to TopTop