Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation

Guo, Ren; Jia, Xiaohui; Ding, Zhen–Bin; Wang, Gang; Jiang, Mengmeng; Li, Bing; Chen, Shanshan; Xia, Baojia; Zhang, Qing; Liu, Jian; Zheng, Ruting; Gao, Zhaobing; Xie, Xin

doi:10.7150/thno.71400

Cited by 33 publications

(25 citation statements)

References 67 publications

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“…Besides macrophages, necroptosis also occurs in other kinds of liver cells during liver fibrogenesis. For example, recent research has proved that Mlkl knockout significantly alleviates BDL-induced mouse liver fibrosis by reducing hepatocyte necroptosis and hepatic stellate cell activation [ 36 ]. All these results indicate that necroptosis is a vital player of cholestatic liver injury/fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis

Shen

Chang

et al. 2023

Cell Death Dis

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Biliary atresia (BA) is a severe inflammatory and fibrosing neonatal cholangiopathy disease characterized by progressive obstruction of extrahepatic bile ducts, resulting in cholestasis and progressive hepatic failure. Cholestasis may play an important role in the inflammatory and fibrotic pathological processes, but its specific mechanism is still unclear. Necroptosis mediated by Z-DNA-binding protein 1 (ZBP1)/phosphorylated-mixed lineage kinase domain-like pseudokinase (p-MLKL) is a prominent pathogenic factor in inflammatory and fibrotic diseases, but its function in BA remains unclear. Here, we aim to determine the effect of macrophage necroptosis in the BA pathology, and to explore the specific molecular mechanism. We found that necroptosis existed in BA livers, which was occurred in liver macrophages. Furthermore, this process was mediated by ZBP1/p-MLKL, and the upregulated expression of ZBP1 in BA livers was correlated with liver fibrosis and prognosis. Similarly, in the bile duct ligation (BDL) induced mouse cholestatic liver injury model, macrophage necroptosis mediated by ZBP1/p-MLKL was also observed. In vitro, conjugated bile acid-glycodeoxycholate (GDCA) upregulated ZBP1 expression in mouse bone marrow-derived monocyte/macrophages (BMDMs) through sphingosine 1-phosphate receptor 2 (S1PR2), and the induction of ZBP1 was a prerequisite for the enhanced necroptosis. Finally, after selectively knocking down of macrophage S1pr2 in vivo, ZBP1/p-MLKL-mediated necroptosis was decreased, and further collagen deposition was markedly attenuated in BDL mice. Furthermore, macrophage Zbp1 or Mlkl specific knockdown also alleviated BDL-induced liver injury/fibrosis. In conclusion, GDCA/S1PR2/ZBP1/p-MLKL mediated macrophage necroptosis plays vital role in the pathogenesis of BA liver fibrosis, and targeting this process may represent a potential therapeutic strategy for BA.

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Section: Discussionmentioning

confidence: 99%

Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis

Shen

Chang

et al. 2023

Cell Death Dis

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“…Necroptosis and MLKL expression are associated with NAFLD development. Previous studies using MLKL knockout mice have shown that MLKL inhibition decreases hepatic inflammation, steatosis, and fibrosis. , In this study, the MLKL inhibitor directly reduced fibrosis in HSCs, suggestive of a mechanism inhibiting NAFLD development via inhibition of immune cell and HSC activities.…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have shown that NSA and TC13172, well-known inhibitors of MLKL, target N-terminal domains to suppress MLKL oligomerization. 18,19 Because MLKL plays a crucial role in necroptosis and necrosis, MLKL inhibitors may alleviate inflammation and liver fibrosis in NAFLD. However, the anti-inflammatory and antifibrotic effects of MLKL inhibitors have not yet been thoroughly evaluated.…”

mentioning

confidence: 99%

Novel Inhibitor of Mixed-Lineage Kinase Domain-Like Protein: The Antifibrotic Effects of a Necroptosis Antagonist

Oh,

Park,

Hong

et al. 2023

ACS Pharmacol. Transl. Sci.

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The pseudokinase mixed-lineage kinase domain-like protein plays a crucial role in programmed cell death via necroptosis. We developed a novel mixed-lineage kinase domain-like inhibitor, P28, which demonstrated potent necroptosis inhibition and antifibrotic effects. P28 treatment directly inhibited mixed-lineage kinase domain-like phosphorylation and oligomerization after necroptosis induction, inhibited immune cell death after necroptosis, and reduced the expression of adhesion molecules. Additionally, P28 treatment reduced the level of activation of hepatic stellate cells and the expression of hepatic fibrosis markers induced by necroptosis stimulation. Unlike the necrosulfonamide treatment, the P28 treatment did not induce cytotoxicity. Finally, the cysteine covalent bonding of P28 was confirmed by liquid chromatography–tandem mass spectrometry.

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“…Liver fibrosis is revealed to be the outcome of multiple processes, such as the production of reactive oxygen species, the release of inflammatory factors, the activation of HSCs, the excessive accumulation of ECM, and angiogenesis. [25] Peptides with the ability to relieve or reverse these processes have been explored as antifibrotic peptides for the treatment of liver fibrosis. Oxidative stress is a key factor that can trigger morphological change and activation of HSCs in the development of liver fibrosis.…”

Section: Antifibrotic Peptides For the Treatment Of Liver Fibrosismentioning

confidence: 99%

Peptide‐Based Nanoarchitectonics for the Treatment of Liver Fibrosis

Huang

Zou

2023

ChemBioChem

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Liver fibrosis is a process of excessive accumulation of extracellular matrix caused by liver injury. Liver fibrosis can progress to cirrhosis or even liver cancer without proper intervention. Until now, no effective therapeutic drugs have been clinically approved for treating liver fibrosis. Hence, the development of safe and effective antifibrotic drugs is particularly important. As a representative biomaterial, peptides have been investigated as key components for constructing antifibrotic nanomaterials given their advantages of biological origination, synthetic availability, and good biocompatibility. Peptides serve as multifunctional motifs in antifibrotic nanomaterials, such as liver‐targeting molecules, antifibrotic molecules, and self‐assembling building blocks for the formation of the nanomaterials. In this review, we focus on peptide‐based nanoarchitectonics for treating liver fibrosis, including nanomaterials modified with liver‐targeting peptides, nanomaterials for the efficient delivery of antifibrotic peptides, and self‐assembled peptide nanomaterials for the delivery of antifibrotic drugs. The design rules of these peptide‐based nanomaterials are described. The antifibrotic mechanisms and effects of these peptide‐based nanomaterials in treating liver fibrosis and related diseases are highlighted. The challenges and future perspectives of using peptide‐based nanoarchitectonics for the treatment of liver fibrosis are discussed. These results are expected to accelerate the rational design and clinical translation of antifibrotic nanomaterials.

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Loss of MLKL ameliorates liver fibrosis by inhibiting hepatocyte necroptosis and hepatic stellate cell activation

Cited by 33 publications

References 67 publications

Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis

Necroptosis of macrophage is a key pathological feature in biliary atresia via GDCA/S1PR2/ZBP1/p-MLKL axis

Novel Inhibitor of Mixed-Lineage Kinase Domain-Like Protein: The Antifibrotic Effects of a Necroptosis Antagonist

Peptide‐Based Nanoarchitectonics for the Treatment of Liver Fibrosis

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