Mechanisms and Prevention in Steatotic Liver Disease

A Special Issue of Metabolites (ISSN 2218-1989) belonging to the section "Endocrinology and Clinical Metabolic Research".

Deadline for manuscript submissions: 20 February 2027 | Viewed by 872

Editor


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Guest Editor
Kansai Medical University Medical Center, Osaka 570-8507, Japan
Interests: steatotic liver disease
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Special Issue Information

Dear Colleagues,

Steatotic liver disease (SLD) has rapidly evolved into a critical global health menace. Its impact extends far beyond the liver, representing a systemic condition that significantly increases the risk of progressive hepatic damage and multi-organ comorbidities, most notably cardiovascular disease. Despite its rising prevalence, the precise molecular triggers that govern the transition from simple steatosis to advanced disease remain partially obscured. To establish robust preventive and therapeutic strategies, there is an urgent need to clarify the fundamental pathogenic mechanisms that drive this progression.

This Special Issue focuses on the diverse array of metabolites that serve as central orchestrators of liver inflammation and fibrosis—the two pivotal hallmarks of SLD progression. We seek to explore how dietary nutrients, systemic metabolic dysfunction, and the gut-liver axis converge to produce bioactive molecules that dictate cellular behavior.

We specifically invite research that elucidates the roles of key pathogenic players, including but not limited to: Pro-inflammatory Drivers: Palmitate, succinate, free cholesterol, and gut-derived lipopolysaccharides (LPS). Fibrotic Catalysts: Succinate, lactate, and advanced glycation end-products (AGEs).

While the primary focus is on the metabolites themselves, we also welcome work that explores how these molecules influence downstream cellular responses, including the modulation of signaling cascades and associated changes in gene expression. By centering on these metabolic "messengers," we aim to bridge the gap between systemic metabolic health and localized tissue injury.

We invite the submission of original research articles, systematic reviews, and clinical trials that provide novel insights into these metabolic drivers. Contributions that offer potential therapeutic targets or innovative diagnostic approaches based on the hepatic metabolome are particularly encouraged.

Dr. Nobuyuki Toshikuni
Guest Editor

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Keywords

  • steatotic liver disease
  • hepatocyte inflammation
  • liver fibrogenesis
  • gut-liver axis metabolites
  • lipotoxicity

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Published Papers (1 paper)

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Review

15 pages, 3755 KB  
Review
Therapeutic Mechanisms of Resmetirom and Semaglutide in MASLD/MASH: A Review of Inflammatory and Fibrotic Metabolites
by Nobuyuki Toshikuni
Metabolites 2026, 16(8), 586; https://doi.org/10.3390/metabo16080586 - 18 Aug 2026
Viewed by 572
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease, and its progressive inflammatory phenotype, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by hepatocellular injury, inflammation, and fibrosis. These processes are closely linked to altered metabolite networks, including lipotoxic lipids, [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease, and its progressive inflammatory phenotype, metabolic dysfunction-associated steatohepatitis (MASH), is characterized by hepatocellular injury, inflammation, and fibrosis. These processes are closely linked to altered metabolite networks, including lipotoxic lipids, oxidized lipid mediators, bile acids, amino acids, acylcarnitines, redox-related metabolites, gut-derived metabolites, and extracellular matrix remodeling products. The recent introduction of resmetirom and semaglutide for MASH with moderate-to-advanced fibrosis provides two complementary models for interpreting these networks. Resmetirom, a liver-directed thyroid hormone receptor-β agonist, primarily enhances intrahepatic lipid handling, mitochondrial fatty acid metabolism, cholesterol turnover, and lipoprotein remodeling. Through this “inside-out” mechanism, resmetirom may reduce hepatocyte lipotoxic stress and secondarily attenuate inflammatory and fibrogenic signaling. Semaglutide, a glucagon-like peptide-1 receptor agonist, mainly acts through systemic metabolic unloading by reducing energy intake, body weight, insulin resistance, and adipose–liver substrate flux. Through this “outside-in” mechanism, semaglutide may improve the hepatic metabolite environment indirectly. However, histological improvement does not by itself establish causal metabolite mediators, and many specific metabolite-level mechanisms remain incompletely defined in human MASH. This review summarizes metabolite networks linked to inflammation and fibrosis in MASLD/MASH, compares the metabolic implications of resmetirom and semaglutide, and discusses how therapeutic metabolomics may support biomarker discovery, patient stratification, and precision pharmacotherapy. Full article
(This article belongs to the Special Issue Mechanisms and Prevention in Steatotic Liver Disease)
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