SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression

Lv, Tingting; Fan, Xiude; He, Chang; Zhu, Suwei; Xiong, Xiaofeng; Yan, Wei; Liu, Mei; Xu, Hongwei; Shi, Ruihua; He, Qin

doi:10.1016/j.redox.2024.103159

Cited by 3 publications

(2 citation statements)

References 56 publications

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“…SLC7A11 decreases reactive oxygen species (ROS) levels and increases α-ketoglutarate (αKG)/proly hydroxylase (PHD) activity, thereby activating the AMPK-mitophagy axis and suppressing the expression of NLRP3 inflammation components. The SLC7A11-ROS/αKG-AMPK axis in hepatocytes is pivotal for controlling MASH progression, whereas Slc7a11 knockdown or knockout aggravates steatohepatitis [ 79 ]. Macrophage stimulating 1 (Mst1) is an upstream regulator of mitophagy that decreases Parkin expression via repression of the AMPK signaling pathway.…”

Section: Role Of Liver Cell Mitophagy In Masld and Liver Fibrosismentioning

confidence: 99%

Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis

Chen,

Jian,

Guo

et al. 2024

Antioxidants

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Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately one-third of the global population. MASLD and its advanced-stage liver fibrosis and cirrhosis are the leading causes of liver failure and liver-related death worldwide. Mitochondria are crucial organelles in liver cells for energy generation and the oxidative metabolism of fatty acids and carbohydrates. Recently, mitochondrial dysfunction in liver cells has been shown to play a vital role in the pathogenesis of MASLD and liver fibrosis. Mitophagy, a selective form of autophagy, removes and recycles impaired mitochondria. Although significant advances have been made in understanding mitophagy in liver diseases, adequate summaries concerning the contribution of liver cell mitophagy to MASLD and liver fibrosis are lacking. This review will clarify the mechanism of liver cell mitophagy in the development of MASLD and liver fibrosis, including in hepatocytes, macrophages, hepatic stellate cells, and liver sinusoidal endothelial cells. In addition, therapeutic strategies or compounds related to hepatic mitophagy are also summarized. In conclusion, mitophagy-related therapeutic strategies or compounds might be translational for the clinical treatment of MASLD and liver fibrosis.

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Section: Role Of Liver Cell Mitophagy In Masld and Liver Fibrosismentioning

confidence: 99%

Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis

Chen,

Jian,

Guo

et al. 2024

Antioxidants

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“…The role of SLC7A11 in fibrosis regulation is controversial, with certain research indicating that its upregulation can inhibit fibrotic pathways and slow the formation of tissue fibrosis, while other research has reached opposite conclusions [27,28]. Lv T et al [29] found that SLC7A11 decreases the levels of reactive oxygen species (ROS) as well as enhances the activity of α-ketoglutarate (αKG)/prolyl hydroxylase (PHD), leading to AMPK pathway activation. Furthermore, by stimulating the AMPK-mitophagy axis, SLC7A11 boosts HSCs activation, which contributes to liver injury and fibrosis progression.…”

Section: Introductionmentioning

confidence: 99%

SLC7A11 Silencing Modulates Ferroptosis and Autophagy to Reduce Sodium Arsenite-Induced Activation of Hepatic Stellate Cells

Ding,

Zhao,

Huang

et al. 2024

Preprint

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Arsenic is a prevalent environmental pollutant with recognized carcinogenic properties. Liver fibrosis is a frequent consequence of arsenic poisoning, with the activation of hepatic stellate cells (HSCs) being a central event. Solute Carrier Family 7 Member 11 (SLC7A11), a pivotal regulator of ferroptosis, may be involved in the process of arsenic-induced liver fibrosis. This study utilized lentiviral vector-mediated SLC7A11 silencing in LX-2 cells (a type of human hepatic stellate cells) to establish an SLC7A11 knockout cell model, which was then exposed to sodium arsenite (NaAsO2). Protein interactions were assessed through Protein Immunoprecipitation (IP), and protein levels were evaluated via Western blot analysis. It was found that NaAsO2 decreased cellular Fe2+ levels and nuclear receptor co-activator 4 (NCOA4) expression, with SLC7A11 silencing reversing these effects. Additionally, IP analysis revealed an interaction between Beclin1 and SLC7A11 proteins in LX-2 cells exposed to NaAsO2. Silencing SLC7A11 attenuated the reduction in Tumor Protein p53(P53), and p-mammalian target of rapamycin (p-mTOR) protein levels, along with the rise in Beclin1, Phosphorylated adenosine monophosphate activated protein kinase (p-AMPK), α-smooth muscle actin (α-SMA) and Fibroblast activation protein-α (FAP) induced by NaAsO2. Consequently, SLC7A11 silencing promoted cellular ferroptosis, reduced autophagy levels through the P53/AMPK/mTOR pathway, and inhibited HSC activation by NaAsO2, potentially mitigating liver fibrosis.

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Unveiling the role of ferroptosis in the progression from NAFLD to NASH: recent advances in mechanistic understanding

Yu,

Song

2024

Front. Endocrinol.

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Non-alcoholic fatty liver disease (NAFLD) is a prevalent and significant global public health issue. Nonalcoholic steatohepatitis (NASH) represents an advanced stage of NAFLD in terms of pathology. However, the intricate mechanisms underlying the progression from NAFLD to NASH remain elusive. Ferroptosis, characterized by iron-dependent cell death and distinguished from other forms of cell death based on morphological, biochemical, and genetic criteria, has emerged as a potential participant with a pivotal role in driving NAFLD progression. Nevertheless, its precise mechanism remains poorly elucidated. In this review article, we comprehensively summarize the pathogenesis of NAFLD/NASH and ferroptosis while highlighting recent advances in understanding the mechanistic involvement of ferroptosis in NAFLD/NASH.

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SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression

Cited by 3 publications

References 56 publications

Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis

Liver Cell Mitophagy in Metabolic Dysfunction-Associated Steatotic Liver Disease and Liver Fibrosis

SLC7A11 Silencing Modulates Ferroptosis and Autophagy to Reduce Sodium Arsenite-Induced Activation of Hepatic Stellate Cells

Unveiling the role of ferroptosis in the progression from NAFLD to NASH: recent advances in mechanistic understanding

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