This review systematically delineates the molecular mechanisms, regulatory networks, and therapeutic implications of mitophagy inabolic dysfunction-associated fatty liver disease and discusses how impaired mitophagy drives the disease progression of MASLD from the perspective of different hepatic cell types.
Abstract
Metabolic dysfunction-associated fatty liver disease (MASLD) represents the most prevalent chronic liver disorder globally, with pathogenesis closely linked to insulin resistance, obesity, and gut microbiota dysbiosis. Mitochondrial dysfunction is central to MASLD progression, and mitophagy-a selective form of autophagy that clears damaged mitochondria-plays a crucial role in maintaining cellular homeostasis. This review systematically delineates the molecular mechanisms, regulatory networks, and therapeutic implications of mitophagy in MASLD. We first outline the core machinery of mitophagy, encompassing both ubiquitin-dependent and ubiquitin-independent pathways. We then discuss how impaired mitophagy drives the disease progression of MASLD from the perspective of different hepatic cell types. Furthermore, we summarize the multilayered upstream regulatory network governing mitophagy in the context of MASLD, involving key signaling pathways, metabolic reprogramming, inflammatory cues, epigenetic modifications, and intercellular crosstalk. Finally, we examine therapeutic strategies targeting mitophagy-including clinical and preclinical agents, natural compounds, physical interventions, and emerging technologies-and highlight the challenges posed by its dualistic nature. Moving forward, integrating spatiotemporal dynamics with precision targeting will be essential to translate mitophagy modulation from mechanistic insight into viable clinical therapies for MASLD.
Despite significant therapeutic advances, T2DM remains a global public health challenge that leads to multiple complications, including cardiovascular, renal, hepatic, and neurodegenerative disorders. Mitochondrial dysfunction and impaired mitophagy remain fundamental, yet incompletely understood, mechanisms driving pancreatic β-cell failure, chronic inflammation, insulin resistance and diabetic complications. Emerging evidence indicates that noncoding RNAs (including microRNAs, long noncoding RNAs, and circular RNAs) are critical regulators of mitophagy and mitochondrial quality control mechanisms across metabolically active tissues. This review comprehensively examines the interplay between mitochondrial dysfunction, mitophagy impairment, and T2DM pathophysiology. It provides an overview of recent mechanistic insights into mitophagy–noncoding RNA interactions in T2DM, emphasizing tissue-specific effects, and highlights the translational potential of mitophagy-associated proteins and regulatory ncRNAs as diagnostic biomarkers and therapeutic targets. By bridging fundamental molecular biology with translational and clinical perspectives, further it provides a comprehensive framework to guide future research, accelerate biomarker discovery, and support the development of personalized interventions aimed at reducing the growing worldwide burden of T2DM and its complications.
Ashish Kothari, M. P. Narayanan, S. Yadav et al.· Biomedicines· 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
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
Cardiovascular disease (CVD) is one of the leading causes of global morbidity and mortality. Its development and progression are closely associated with mitochondrial dysfunction, sterile inflammation, and immunometabolic dysregulation. Mitophagy, a key mechanism of mitochondrial quality control, maintains mitochondrial homeostasis by selectively removing damaged mitochondria. However, either insufficient or excessive mitophagy may disrupt cellular metabolism, promote ROS production and mitochondrial DNA (mtDNA) release, and activate inflammatory signaling pathways, thereby aggravating cardiovascular injury. Increasing evidence indicates that mitophagy is closely linked to pyroptosis and macrophage polarization. Impaired mitophagy can enhance inflammasome activation and gasdermin-mediated pyroptosis. In turn, inflammatory mediators released during pyroptosis may further impair mitochondrial quality control, forming a self-amplifying inflammatory loop. Meanwhile, mitophagy regulates macrophage metabolic reprogramming and phenotypic switching, thereby influencing the balance between pro-inflammatory M1-like responses and reparative M2-like functions. This review summarizes the molecular mechanisms underlying the crosstalk among mitophagy, pyroptosis, and macrophage polarization in CVD, with particular emphasis on myocardial infarction (MI) and myocardial ischemia-reperfusion injury. Current evidence suggests that restoring appropriate mitophagic flux, inhibiting aberrant pyroptosis, and reshaping macrophage phenotypes may help alleviate inflammatory injury and adverse cardiac remodeling. This review aims to provide a mechanistic framework for immunometabolic regulation in CVD and to support the development of precision therapeutic strategies targeting mitochondrial quality control and inflammatory cell responses.
Jie-Ying Yuan, Ting-Ru Ji, Ru-Quan Chen et al.· Frontiers in Cardiovascular...· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disorder worldwide, affecting approximately one-third of the population and increasing the risk of severe hepatic and cardiovascular complications. Growing evidence indicates that MASLD is a systemic disease in which epigenetic changes-including DNA and RNA methylation as well as histone modifications-drive its progression by integrating metabolic and inflammatory signals across organs. This review introduces the concept of "networked epigenome cascades" and highlights how epigenetic alterations in extrahepatic metabolic organs contribute to insulin resistance (IR) and systemic inflammation. MASLD is thereby reframed as a disorder of systemic epigenomic miscommunication rather than a liver-only disease. We further discuss preclinical and emerging interventions, with an emphasis on natural compounds that modulate epigenomic regulation, while noting the uncertainties that remain regarding their translational potential for MASLD. By positioning the epigenome as a central mechanism, this review underscores its promise for biomarker development and mechanistically targeted interventions, although robust validation in humans is still required.
Shu-Rui Yang, Zhong-Yu Huang, Sanchun Tan et al.· Obesity Reviews· 0 citations
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
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
