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Molecular Advances in Metabolic Dysfunction-Associated Steatotic Liver Disease
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Molecular Advances in Metabolic Dysfunction-Associated Steatotic Liver Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 20 April 2026 | Viewed by 5328

Special Issue Editors

Prof. Dr. Rifaat Safadi

E-Mail Website
Guest Editor
The Liver Institute, Hadassah Hebrew University Hospital, Jerusalem IL-91120, Israel
Interests: liver and bowel diseases; metabolic syndrome; gut–liver axis; fibrosis biomarkers
Dr. Johnny Amer

E-Mail Website
Co-Guest Editor
The Liver Institute, Hadassah Hebrew University Hospital, Jerusalem IL-91120, Israel
Interests: cell biology; molecular biology; liver diseases; hematological diseases; immunology

Special Issue Information

Dear Colleagues,

Metabolic dysfunction-associated steatotic liver disease (MASLD) represents the leading cause of chronic liver disease worldwide and is a growing contributor to extrahepatic complications, including cardiovascular disease and hepatocellular carcinoma. Despite advances in epidemiology and clinical stratification, substantial gaps remain in the mechanistic understanding and molecular targeting of MASLD. This Special Issue seeks to showcase innovative research that elucidates the molecular drivers of MASLD initiation and progression—ranging from hepatocellular lipotoxicity, insulin resistance, and mitochondrial dysfunction to gut–liver axis signaling and inflammatory cascades.

We welcome original research and reviews spanning basic, translational, and early-stage clinical studies. Submissions utilizing molecular approaches in preclinical models, patient biospecimens, or integrated omics platforms are particularly encouraged. In addition, the Special Issue will highlight studies that translate molecular findings into diagnostic biomarkers, therapeutic targets, and risk stratification tools. Our aim is to bring together cutting-edge mechanistic insights and clinically relevant innovation to advance the early detection, personalized management, and prevention of MASLD and its complications.

Prof. Dr. Rifaat Safadi
Dr. Johnny Amer
Guest Editors

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-blind 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

  • MASLD (metabolic dysfunction-associated steatotic liver disease)
  • lipotoxicity
  • inflammation
  • mitochondrial dysfunction
  • gut–liver axis
  • liver–spleen axis
  • fibrosis biomarkers
  • translational hepatology
  • precision liver medicine
  • insulin resistance
  • molecular therapeutics

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Published Papers (5 papers)

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Research

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10 pages, 865 KB  
Article
Unraveling the Role of BAG3 in Hepatic Fibrosis: Genetic and Biomarker Insights in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)
by Benedetta Maria Motta, Alessandra Rosati, Mariano Festa, Anna Basile, Tommaso Sarcina, Maria Caterina Turco and Marcello Persico
Int. J. Mol. Sci. 2025, 26(23), 11286; https://doi.org/10.3390/ijms262311286 - 22 Nov 2025
Viewed by 220
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health burden, with hepatic fibrosis being the strongest determinant of clinical outcomes. While genetic variants such as PNPLA3 and TM6SF2 are recognized drivers of disease progression, the downstream molecular mediators linking genetic susceptibility [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health burden, with hepatic fibrosis being the strongest determinant of clinical outcomes. While genetic variants such as PNPLA3 and TM6SF2 are recognized drivers of disease progression, the downstream molecular mediators linking genetic susceptibility to fibrogenesis remain unclear. This study investigated the role of the stress-response co-chaperone BAG3 as a circulating biomarker of hepatic fibrosis and its association with PNPLA3 and TM6SF2 genotypes. In a well-characterized Southern European cohort of 146 MASLD patients, liver fibrosis was assessed using the FIB-4 index, serum BAG3 levels were quantified by ELISA, and genotyping for PNPLA3 and TM6SF2 variants was performed. BAG3 concentrations were significantly higher in patients with advanced disease and correlated positively with FIB-4 values. Carriers of the TM6SF2 risk allele exhibited increased BAG3 levels, and a cumulative increase was observed with multiple PNPLA3 and TM6SF2 risk alleles. These findings suggest that BAG3 may represent a potential, non-invasive biomarker reflecting fibrogenic burden and a mechanistic link between genetic risk and hepatic fibrosis in MASLD. Full article
(This article belongs to the Special Issue Molecular Advances in Metabolic Dysfunction-Associated Steatotic Liver Disease)
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20 pages, 6791 KB  
Article
Hepatic Histopathological Benefit, Microbial Cost: Oral Vancomycin Mitigates Non-Alcoholic Fatty Liver Disease While Disrupting the Cecal Microbiota
by Gül Çirkin, Selma Aydemir, Burcu Açıkgöz, Aslı Çelik, Yunus Güler, Müge Kiray, Başak Baykara, Ener Çağrı Dinleyici and Yeşim Öztürk
Int. J. Mol. Sci. 2025, 26(17), 8616; https://doi.org/10.3390/ijms26178616 - 4 Sep 2025
Viewed by 1164
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) encompasses a spectrum of liver conditions and involves gut–liver axis crosstalk. We aimed to evaluate whether oral vancomycin modifies liver injury and the cecal microbiota in a methionine–choline-deficient (MCD) diet model of NASH. Male [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) encompasses a spectrum of liver conditions and involves gut–liver axis crosstalk. We aimed to evaluate whether oral vancomycin modifies liver injury and the cecal microbiota in a methionine–choline-deficient (MCD) diet model of NASH. Male C57BL/6J mice (n = 28) were block-randomized to four groups (n = 7 each) for 10 weeks: standard diet (STD); MCD diet; STD + vancomycin (VANC); and MCD + VANC (2 mg/mouse ≈ 50 mg/kg, every 72 h). After 10 weeks, liver tissues were analyzed for histological changes, cytokine levels [interleukin-6 (IL-6), interleukin-8 (IL-8), transforming growth factor beta 1 (TGF-β1)], and immunohistochemical markers [ubiquitin and cytokeratin 18 (CK18)]. Cecal microbiota composition was evaluated with 16S ribosomal RNA (rRNA) sequencing. The MCD reproduced key NASH features (macrovesicular steatosis, lobular inflammation). Vancomycin shifted steatosis toward a microvesicular pattern and reduced hepatocyte injury: CK18 and ubiquitin immunoreactivity were decreased in MCD + VANC vs. MCD, and hepatic IL-8 and TGF-β1 levels were lower in MCD + VANC vs. STD. Taxonomically, STD mice had Lactobacillus-rich microbiota. The MCD diet alone reduced alpha diversity (α-diversity), modestly lowered Firmicutes and increased Desulfobacterota/Fusobacteriota. Vancomycin alone caused a much larger collapse in richness, depleting Gram-positive commensals and promoting blooms of Escherichia–Shigella, Klebsiella, Parabacteroides, and Akkermansia. In the MCD + VANC group, vancomycin profoundly remodeled the microbiota, eliminating key commensals (e.g., Lactobacillus) and enriching Desulfobacterota, Fusobacteriota, and Campylobacterota. Oral vancomycin in the MCD model of NASH improved liver injury markers and altered steatosis morphology, but concurrently reprogrammed the gut into a low-diversity, pathobiont-enriched ecosystem with near-loss of Lactobacillus. These findings highlight a therapeutic trade-off—hepatic benefit accompanied by microbiome cost—that should guide microbiota-targeted strategies for NAFLD/NASH. Full article
(This article belongs to the Special Issue Molecular Advances in Metabolic Dysfunction-Associated Steatotic Liver Disease)
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16 pages, 2344 KB  
Article
Circulating FGF21 and Ketone Bodies Modify the Risk of MASLD and Mortality: Insights from the PREVEND Cohort Study
by Mateo Chvatal-Medina, Yakun Li, Wendy A. Dam, Margery A. Connelly, Han Moshage, Stephan J. L. Bakker, Robin P. F. Dullaart and Adrian Post
Int. J. Mol. Sci. 2025, 26(11), 5059; https://doi.org/10.3390/ijms26115059 - 24 May 2025
Viewed by 1224
Abstract
Fibroblast growth factor 21 (FGF21) and ketone bodies are markers of metabolic dysregulation, independently associated with metabolic-dysfunction-associated steatotic liver disease (MASLD) and mortality. We studied their interaction with MASLD and all-cause mortality in 6025 participants from the Prevention of Renal and Vascular End-stage [...] Read more.
Fibroblast growth factor 21 (FGF21) and ketone bodies are markers of metabolic dysregulation, independently associated with metabolic-dysfunction-associated steatotic liver disease (MASLD) and mortality. We studied their interaction with MASLD and all-cause mortality in 6025 participants from the Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort. Plasma FGF21 (immunoassay) and ketone body concentrations (nuclear magnetic resonance spectroscopy) were measured at baseline. A Fatty Liver Index ≥60 was used as a proxy of MASLD. Logistic regression assessed associations with MASLD, and Cox models evaluated all-cause mortality over a median follow-up of 10.3 years. FGF21 and ketone bodies were not correlated (r = 0.02, p = 0.06), but FGF21 (OR: 1.93 [1.81–2.05], p < 0.001) and ketone bodies (OR: 1.29 [1.19–2.05], p < 0.001) were independent of each other associated with MASLD, with a positive interaction (p = 0.004). Higher FGF21 (HR: 1.24, 95% CI: 1.16–1.32, p < 0.001) and ketone bodies (HR: 1.46, 95% CI: 1.34–1.59, p < 0.001) were associated with mortality, as well as with a positive interaction (p = 0.038). After adjustment for potential confounders, only ketone bodies remained independently associated, while the association of FGF21 became dependent on ketone body levels (interaction p = 0.005). These biomarkers may serve as integrated metabolic stress markers, improving risk stratification for MASLD and adverse outcomes. Full article
(This article belongs to the Special Issue Molecular Advances in Metabolic Dysfunction-Associated Steatotic Liver Disease)
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Review

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32 pages, 2385 KB  
Review
Cardiovascular Disease in the Context of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): A Comprehensive Narrative Review
by Attia Mustafa, Chris Kite, Lukasz Lagojda, Alexander Dallaway, Kamaljit Kaur Chatha, Nwe Ni Than, Eva Kassi, Ioannis Kyrou and Harpal S. Randeva
Int. J. Mol. Sci. 2025, 26(23), 11275; https://doi.org/10.3390/ijms262311275 - 21 Nov 2025
Viewed by 470
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic hepatic disease with a rising global prevalence (25–38% of the general population). As a new term, MASLD was introduced in 2023 to replace the previous nomenclature of non-alcoholic fatty liver disease (NAFLD) and metabolic [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic hepatic disease with a rising global prevalence (25–38% of the general population). As a new term, MASLD was introduced in 2023 to replace the previous nomenclature of non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated fatty liver disease (MAFLD). This new term/definition introduced changes in the diagnostic criteria and underscores the direct link between cardio-metabolic risk and this prevalent liver disease. In this context, the present review examines the clinical and pathophysiological links between MASLD and cardiovascular disease (CVD), providing a robust evidence synthesis of primarily systematic review data on the association between MASLD and coronary artery disease (CAD), atrial fibrillation (AF), and heart failure (HF). This association appears to be not only synergistic, but also independent of other known CVD risk factors, highlighting MASLD as a key cardio-metabolic risk factor that merits prompt diagnosis and treatment. The development of MASLD-related cardiovascular morbidity increases with the severity of the underlying hepatic pathology, particularly with progression to steatohepatitis and fibrosis. Notably, growing evidence highlights the links between MASLD and CVD through cardiac structural, electrical, and functional alterations that can progress to CAD, AF, and new-onset HF. Recognizing these links in clinical practice underscores the importance of early detection and multi-disciplinary management of MASLD to prevent disease progression and CVD complications. Full article
(This article belongs to the Special Issue Molecular Advances in Metabolic Dysfunction-Associated Steatotic Liver Disease)
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16 pages, 1275 KB  
Review
MASLD Under the Microscope: How microRNAs and Microbiota Shape Hepatic Metabolic Disease Progression
by Clelia Asero, Maria Stella Franzè, Irene Cacciola and Sebastiano Gangemi
Int. J. Mol. Sci. 2025, 26(17), 8633; https://doi.org/10.3390/ijms26178633 - 4 Sep 2025
Viewed by 1843
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most prevalent cause of chronic liver disease worldwide. Its pathogenesis is complex and not yet fully elucidated but is commonly explained by the “multiple hit” hypothesis, which suggests that pathological behaviours interact with an [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most prevalent cause of chronic liver disease worldwide. Its pathogenesis is complex and not yet fully elucidated but is commonly explained by the “multiple hit” hypothesis, which suggests that pathological behaviours interact with an unfavourable genetic background and the presence of cardiovascular comorbidities. Recent evidence has highlighted a potential role of the gut microbiota in the onset and progression of MASLD to metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC), potentially driven by epigenetic modifications mediated by microRNAs (miRNAs). MiRNAs are small, non-coding RNAs that regulate gene expression both intra- and extracellularly. Notably, emerging data suggests a bidirectional communication between the gut microbiota and the host, mediated by miRNAs via exosomes and outer membrane vesicles. The primary aim of this review is to explore the epigenetic crosstalk between the host and the gut microbiota through miRNA expression, with the goal of identifying specific pathways involved in MASLD development and natural history. A secondary objective is to evaluate the potential applications of artificial intelligence in the analysis of these complex host–microbiota interactions, to standardize the evaluation of microbiota and to create a model of the epigenetic changes in metabolic liver disease. Full article
(This article belongs to the Special Issue Molecular Advances in Metabolic Dysfunction-Associated Steatotic Liver Disease)
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