Jul 2026· Frontiers in Cell and Developmental Biology· Vol 14· 0 citations· 123 references
Medicine
TL;DR
It is concluded that targeting inter-organelle interfaces, rather than isolated metabolic reactions, offers a genetically supported and mechanistically rational path forward in MASH.
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is increasingly recognized as a disorder of inter-organelle communication, in which the lipid droplet (LD)–mitochondria interface serves as a central metabolic hub. Under physiological conditions, this interface couples LD lipolysis to mitochondrial β-oxidation, ensuring that fatty-acid release matches energy demand. In MASH, chronic nutrient excess disrupts this coupling, driving the accumulation of lipotoxic metabolites, activating innate immune pathways, and perpetuating hepatocellular injury and inflammation. Among the proteins proposed to operate at this LD-mitochondria interface, hydroxysteroid 17β-dehydrogenase 13 (HSD17B13) has emerged as a particularly compelling candidate. A loss-of-function human genetic variant is associated with reduced risk of chronic liver disease, motivating therapeutic development; however, whether HSD17B13 directly governs physical organelle apposition or merely influences lipid flux remains unresolved, highlighting a key gap between human genetic evidence and experimental models. This review synthesizes current understanding of the molecular organization of the LD-mitochondria axis, critically examines the proposed scaffolding and enzymatic functions of HSD17B13, and discusses the therapeutic potential of restoring organelle communication as a unified strategy in MASH. We conclude that targeting inter-organelle interfaces, rather than isolated metabolic reactions, offers a genetically supported and mechanistically rational path forward.
It is highlighted that dysregulated mitophagy and mitochondrial fragmentation promote lipid accumulation and inflammation, whereas the abnormal formation of mitochondria-associated membranes (MAMs) exacerbates calcium overload and oxidative stress, and short-chain fatty acids and bile acids derived from the gut differentially modulate mitochondrial bioenergetics.
Jing-Wen Liu, Ke-Wei Li, Yinggui Deng et al.· Pharmacological Research· 0 citations
Metabolic dysfunction‐associated steatotic liver disease (MASLD) is the most common chronic liver condition worldwide and a major contributor to cirrhosis and hepatocellular carcinoma (HCC). While metabolic triggers such as obesity and insulin resistance are key drivers of MASLD, growing evidence has identified defects in intracellular quality control—namely impaired autophagy—as central mechanisms governing disease progression. Autophagy, including selective lipophagy and mitophagy, plays a crucial role in hepatic lipid turnover and mitochondrial homeostasis. In MASLD, disruption of these processes contributes to lipid accumulation and oxidative stress, leading to hepatocellular damage (ballooning), fibrogenesis, and HCC. Experimental studies linked impaired autophagic flux to liver injury, and emerging evidence from human genetics suggests that inter‐individual inherited variation influences MASLD susceptibility by impairing autophagy. Specifically, main genetic MASLD modifiers such as the p.I148M variant of Patatin‐like phospholipase domain‐containing protein 3 (PNPLA3) and loss‐of‐function and hypomorphic variants in autophagy‐related gene 7 (ATG7), a core autophagy gene, predispose to ballooning, fibrosis, and HCC. By outlining emerging therapies that restore autophagic flux and reduce steatosis, lipotoxicity, and fibrosis, we propose an integrated precision‐medicine model based on genetics and autophagy dynamics biomarkers, offering a new framework for personalized therapeutics.
A. Cazzaniga, Silvia Frigo, Alessandro Cherubini et al.· Liver international (Print)· 1 citation
Metabolic dysfunction-associated fatty liver disease (MASLD) is a major global health challenge characterized by metabolic imbalance, inflammation, and oxidative stress, yet effective targeted therapies remain limited. Lipoprotein-associated phospholipase A2 (Lp-PLA2) has emerged as a potential regulator of metabolic disorders, but its role and therapeutic relevance in MASLD remain unclear. Integrative bioinformatics analysis of human liver transcriptomic datasets combined with virtual screening, network pharmacology, and molecular docking identified chebulinic acid (CA) as a potential Lp-PLA2-targeting compound. The therapeutic effects and underlying mechanisms of CA were investigated using high-fat diet (HFD)-induced MASLD mouse models and free fatty acid (FFA)-treated Huh7 hepatocytes using metabolic profiling, histological analysis, Seahorse bioenergetic assessment, adeno-associated virus (AAV)-mediated gene overexpression, and cellular thermal shift assay. Lp-PLA2 was identified as a key regulator associated with MASLD progression and metabolic pathway dysregulation. CA exhibited strong binding affinity to Lp-PLA2 and significantly ameliorated metabolic dysfunction, hepatic steatosis, inflammation, and oxidative stress in both in vivo and in vitro models. Mechanistically, CA restored mitochondrial respiration and glycolytic capacity while reducing abnormal HK2 expression. HK2 overexpression abolished the protective effects of CA, indicating that excessive HK2 expression contributes to metabolic imbalance under metabolic stress conditions. Furthermore, CA CA binding to Lp-PLA2 through the Glu304 residue was required for its metabolic protective effects and was associated with regulation of the Lp-PLA2-HK2-associated pathway. This study identifies Lp-PLA2-associated HK2 dysregulation as a potential contributor to MASLD metabolic dysfunction and demonstrates that CA improves hepatic metabolic homeostasis through modulation of Lp-PLA2 signaling.
Yinghui Wang, Guo-Chun Zhang, Xicheng Jiang et al.· Journal of Nutritional Bioch...· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide, encompassing a spectrum from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis and hepatocellular carcinoma. Increasing evidence indicates that disease progression is driven not by hepatic triglyceride accumulation alone but by the metabolic partitioning of excess fatty acids between adaptive and maladaptive pathways. Ketogenesis, traditionally viewed as a fasting-induced mechanism for disposing of excess acetyl-CoA, is now recognized as a key regulator of hepatic metabolic homeostasis, coordinating mitochondrial substrate utilization, carbon flux and systemic metabolic adaptation. In addition to serving as oxidative fuels, ketone bodies, particularly β-hydroxybutyrate, function as signalling metabolites that modulate inflammation, oxidative stress, mitochondrial function and epigenetic regulation. Despite increased fatty acid delivery in obesity and insulin resistance, ketogenic capacity becomes progressively impaired during MASLD, promoting mitochondrial acetyl-CoA accumulation, oxidative stress and diversion of carbon toward lipotoxic lipid synthesis while reducing protective β-hydroxybutyrate signalling. This review examines ketogenesis as an integrative metabolic checkpoint linking fatty acid oxidation, lipid metabolism, mitochondrial function and immune signalling in MASLD. We discuss how impaired ketogenic flux contributes to hepatocellular injury, fibrosis and metabolic inflexibility, and evaluate the therapeutic potential of restoring ketogenesis to prevent disease progression.
The PDK4–PDH axis provides a useful framework for understanding how mitochondrial fuel restriction may contribute to chronic inflammation across aging tissues, including skeletal muscle, adipose tissue, brain, and kidney, and therapeutic strategies aimed at restoring mitochondrial function to suppress chronic inflammation and preserve healthspan are evaluated.
Md Riad Chowdhury, G. Jeong, In-Kyu Lee· Cells· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults globally, yet therapeutic options remain limited. Macrophage metabolic reprogramming is increasingly recognized as an important contributor to disease progression. Hepatic macrophages from resident Kupffer cells (KCs) to infiltrating monocyte-derived macrophages (MoMFs) and triggering receptor expressed on myeloid cells 2 (TREM2) + lipid-associated macrophages (LAMs) shift their bioenergetic profile from fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) toward aerobic glycolysis. This review maps the metabolic circuits driving macrophage-mediated inflammation in MASLD. We delineate how tricarboxylic acid (TCA) cycle disruption generates signaling metabolites that enforce glycolytic commitment through hypoxia-inducible factor stabilization, how metabolic-epigenetic coupling perpetuates inflammatory programs, and how the failure of repair mechanisms and mitochondrial quality control accelerates tissue damage. Notably, the IRG1-itaconate axis exhibits a dynamic U-shaped trajectory across MASLD stages: itaconate levels decrease during early steatosis due to Kupffer cell loss, but subsequently rise markedly during MASH as infiltrating macrophages upregulate IRG1 expression, representing a compensatory yet insufficient anti-inflammatory response. We further examine how these metabolic states evolve across disease stages, from simple steatosis through steatohepatitis and fibrosis to cirrhosis, and assess the therapeutic potential of metabolic interventions. Recent FDA accelerated approvals of resmetirom and semaglutide for selected adults with non-cirrhotic MASH and F2-F3 fibrosis have expanded the therapeutic landscape. Their clinical benefits are primarily supported by histological endpoints; whether modulation of hepatic macrophage metabolism contributes directly to these benefits remains to be established. Emerging evidence indicates that macrophage metabolic states retain plasticity and can be pharmacologically reprogrammed, with single-cell metabolomics poised to guide precision therapeutic strategies.
Li Zhu, Bo Wu· Frontiers in Immunology· 0 citations
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