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Metabolic Dysfunction-Associated Steatotic Liver Disease: From Basic Research to Clinical Approaches

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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: 20 August 2025 | Viewed by 5716

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Dr. Barbara Toffoli

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Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy
Interests: hepatic steatosis; diabetes and its complications; obesity
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Dear Colleagues,

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern, and it is considered the most common cause of chronic liver disease. A positive diagnosis of MASLD is based on the presence of hepatic steatosis coupled with at least one cardiometabolic risk factor and no other distinguishable cause.

MASLD includes a wide range of liver injuries and can lead to severe conditions such as cirrhosis and liver cancer. Its presence is associated with an increased susceptibility to mortality across different causes. Despite the prevalence of MASLD, a specific approved pharmaceutical compound effective for its treatment is still lacking. Being a complex disease involving genetic susceptibility and environmental factors, an ideal treatment approach for MASLD should target various aspects, such as steatosis reduction, improvement in liver functionality, and protection from other comorbidities. For this purpose, it is critical to fully understand the pathogenesis of MASLD, develop new strategies targeting selective pathways for its prevention or delayed progression, and identify risk factors for early diagnosis.

This Special Issue aims to present a collection of articles related to MASLD from basic research to clinical approaches. Comprehensive studies summarizing the latest findings on clinical trials and studies providing new insights into the cellular and molecular mechanisms involved in MASLD are welcome.

Dr. Barbara Toffoli
Guest Editor

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Keywords

metabolic dysfunction-associated steatotic liver disease (MASLD)
steatosis
obesity
type 2 diabetes mellitus
therapeutic targets and interventions

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Published Papers (4 papers)

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Research

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14 pages, 855 KiB

Open AccessArticle

PNPLA3 Polymorphism Is Inversely Correlated with Aortic Stiffness in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease Without Fibrosis

by Barbara Toffoli, Consuelo Comar, Andrea Grillo, Vincenzo Barbato, Emanuele Vincis, Veronica Baldi, Silvia Berti, Teresa Volpato, Francesca Zorat, Saveria Lory Crocè, Giacomo Emmi, Bruno Fabris, Massimo Puato and Stella Bernardi

Int. J. Mol. Sci. 2025, 26(7), 3256; https://doi.org/10.3390/ijms26073256 - 1 Apr 2025

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) corresponds to the condition of increased hepatic fat levels, which is the leading cause of hepatic failure and carcinoma. It is also an independent risk factor for cardiovascular disease (CVD) and mortality. MASLD can be due to obesity with insulin resistance and/or genetic predisposition, i.e., polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene. PNPLA3 polymorphism has been associated with increased hepatic fat levels, fibrosis, cirrhosis, and hepatocellular carcinoma, while its association with CVD remains to be fully understood. The aim of the current study was to examine whether the vascular phenotype of patients with MASLD differed between carriers and noncarriers of the PNPLA3 polymorphism. Adult patients with MASLD underwent clinical assessment, PNPLA3 genotyping, arterial tonometry for aortic stiffness measurement, and ultrasound examination of carotid arteries. In total, 117 patients with MASLD and no fibrosis (median hepatic stiffness was 4.71 kPa) were recruited. Carriers of the PNPLA3 polymorphism were younger and exhibited higher levels of ALT and APRI, as compared to wild-type subjects. On the other hand, carriers of the PNPLA3 polymorphism had not only a better metabolic profile (i.e., lower glucose and glycated hemoglobin) but also lower blood pressure, carotid intima-media thickness (IMT), and cardiovascular risk. In addition, PNPLA3 polymorphism was negatively correlated with aortic stiffness, which is a marker of arteriolosclerosis and vascular ageing. Our data are consistent with previous observations that in case of genetically-driven MASLD, there is an inverse association with common predictors of CVD. Our data support the view that the main contributors to CVD risk in patients with MASLD remain conventional cardiometabolic risk factors (i.e., age, glucose) that are more likely to be found in metabolic syndrome-related MASLD rather than genetically-driven MASLD, at least in the first stages of the disease. Full article

(This article belongs to the Special Issue Metabolic Dysfunction-Associated Steatotic Liver Disease: From Basic Research to Clinical Approaches)

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22 pages, 3249 KiB

Open AccessArticle

FLAME: Training and Validating a Newly Conceived Model Incorporating Alpha-Glutathione-S-Transferase Serum Levels for Predicting Advanced Hepatic Fibrosis and Acute Cardiovascular Events in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

by Marcello Dallio, Mario Romeo, Fiammetta Di Nardo, Paolo Vaia, Carmine Napolitano, Lorenzo Ventriglia, Annachiara Coppola, Alessia Silvestrin, Simone Olivieri and Alessandro Federico

Int. J. Mol. Sci. 2025, 26(2), 761; https://doi.org/10.3390/ijms26020761 - 17 Jan 2025

Cited by 1 | Viewed by 859

Abstract

Alpha-Glutathione-S-transferase (alphaGST) is a liver enzyme whose serum levels increase with the worsening of fibrosis in alcoholic and viral chronic hepatitis. Its usefulness in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) remains unexplored. From January 2016 to December 2017, 200 patients with MASLD and 30 controls were enrolled. AlphaGST serum levels were measured. Variables related to advanced fibrosis (AF) were selected via Principal Component Analysis (PCA), and the best cut-off (BCO) was estimated using ROC analysis. Liver stiffness measurement (LSM), NAFLD fibrosis (NFS), Fibrosis-4 (FIB-4), and BMI-AST/ALT Ratio-Diabetes (BARD) scores were determined. The first acute cardiovascular events (ACE) in ACE-naïve subjects were recorded over five years. A validation cohort of 60 MASLD patients was enrolled from January 2018 to May 2019 and followed for five years. AlphaGST levels increased with fibrosis stage (p < 0.0001) in both cohorts, showing high accuracy in predicting AF (TrC: AUC 0.89, VlC: AUC 0.89). PCA-selected variables were HbA1c, HDL, and alphaGST, forming the “FLAME” model. FLAME showed superior predictive performance for AF and ACEs compared to other models and scores. FLAME represents a novel tool that accurately predicts AF and ACEs in MASLD. Full article

(This article belongs to the Special Issue Metabolic Dysfunction-Associated Steatotic Liver Disease: From Basic Research to Clinical Approaches)

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15 pages, 2088 KiB

Open AccessArticle

Mesenchymal Stem Cell-Derived Exosomes Attenuate Hepatic Steatosis and Insulin Resistance in Diet-Induced Obese Mice by Activating the FGF21-Adiponectin Axis

by Bobae Kim, Rwubuzizi Ronaldo, Beet-Na Kweon, Solhee Yoon, Yein Park, Jea-Hyun Baek, Jung Min Lee and Chang-Kee Hyun

Int. J. Mol. Sci. 2024, 25(19), 10447; https://doi.org/10.3390/ijms251910447 - 27 Sep 2024

Viewed by 1788

Abstract

Exosomes derived from mesenchymal stem cells have shown promise in treating metabolic disorders, yet their specific mechanisms remain largely unclear. This study investigates the protective effects of exosomes from human umbilical cord Wharton’s jelly mesenchymal stem cells (hWJMSCs) against adiposity and insulin resistance in high-fat diet (HFD)-induced obese mice. HFD-fed mice treated with hWJMSC-derived exosomes demonstrated improved gut barrier integrity, which restored immune balance in the liver and adipose tissues by reducing macrophage infiltration and pro-inflammatory cytokine expression. Furthermore, these exosomes normalized lipid metabolism including lipid oxidation and lipogenesis, which alleviate lipotoxicity-induced endoplasmic reticulum (ER) stress, thereby decreasing fat accumulation and chronic tissue inflammation in hepatic and adipose tissues. Notably, hWJMSC-derived exosomes also promoted browning and thermogenic capacity of adipose tissues, which was linked to reduced fibroblast growth factor 21 (FGF21) resistance and increased adiponectin production. This process activated the AMPK-SIRT1-PGC-1α pathway, highlighting the role of the FGF21–adiponectin axis. Our findings elucidate the molecular mechanisms through which hWJMSC-derived exosomes counteract HFD-induced metabolic dysfunctions, supporting their potential as therapeutic agents for metabolic disorders. Full article

(This article belongs to the Special Issue Metabolic Dysfunction-Associated Steatotic Liver Disease: From Basic Research to Clinical Approaches)

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Review

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15 pages, 1634 KiB

Open AccessReview

RANK–RANKL–OPG Axis in MASLD: Current Evidence Linking Bone and Liver Diseases and Future Perspectives

by Federico Monti, Federica Perazza, Laura Leoni, Bernardo Stefanini, Silvia Ferri, Francesco Tovoli, Guido Zavatta, Fabio Piscaglia, Maria Letizia Petroni and Federico Ravaioli

Int. J. Mol. Sci. 2024, 25(17), 9193; https://doi.org/10.3390/ijms25179193 - 24 Aug 2024

Cited by 2 | Viewed by 2293

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD)—and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage—corresponds to the liver’s involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication. Full article

(This article belongs to the Special Issue Metabolic Dysfunction-Associated Steatotic Liver Disease: From Basic Research to Clinical Approaches)

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