YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis

Zhang, Jing; Zheng, Yongping; Wang, Yun; Wang, Jin; Sang, Aming; Song, Xuemin

doi:10.3389/fimmu.2022.884362

Cited by 29 publications

(24 citation statements)

References 45 publications

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“…Ferroptosis is a regulated cell death mediated by redox imbalance, which is intimately regulated by Nrf2 and its downstream targeted genes [ 29 ]. Several lines of study have revealed that ferroptosis serves a pathogenic role in sepsis-induced ALI [ 40 , 41 , 42 ]. Uridine was extensively reported to exhibit antioxidant effect and regarded as an antioxidative metabolite [ 18 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Lai

Song

Gao

et al. 2023

IJMS

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Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis.

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Section: Discussionmentioning

confidence: 99%

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Lai

Song

Gao

et al. 2023

IJMS

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“…Alveolar epithelial cells, a critical component of the alveolar epithelial-endothelial barrier, play central roles in the pathogenesis of ALI. Ferroptosis was reported to participate in the injury of alveolar epithelial cells, which is induced by LPS [ 9 ]. Therefore, we next detect the effect of PCTR1 on LPS-induced ferroptosis in pulmonary epithelial cell line H1299.…”

Section: Resultsmentioning

confidence: 99%

“…The majority of previous research has focused on nuclear factor-erythroid-2-related factor 2 (Nrf2), which translocates into the nucleus to elevate the expression level of GPX4, resulting in ferroptosis inhibition [ 39 ]. Knockout of Yes-associated protein 1 (YAP1), a key regulator of the Hippo signaling pathway, accelerated ferroptosis and exacerbated CLP-induced ALI by decreasing the expression of GPX4 [ 9 ]. Currently, several studies have proposed that CREB is involved in the regulation of GPX4 transcription, making CREB an important focus of ferroptosis research.…”

Section: Discussionmentioning

confidence: 99%

“…Biochemically, the mechanisms underlying ferroptosis mainly include intracellular iron storage, GSH depletion, GPX4 inactivation and lipid peroxidation [ 5 – 8 ]. During ferroptosis in ALI, the production of lipid ROS induced by iron overload and dysfunction of the antioxidant system lead to the destruction of pulmonary epithelial cells and pulmonary vascular endothelial cells [ 9 , 10 ]. In addition, ferroptosis has attracted tremendous interest for its unique correlation with a number of organ injuries during sepsis, including cardiovascular dysfunction, liver injury and kidney injury [ 11 – 14 ].…”

Section: Introductionmentioning

confidence: 99%

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Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Chen

Tian

et al. 2023

J Transl Med

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Background Acute lung injury (ALI) is a common and serious complication of sepsis with high mortality. Ferroptosis, categorized as programmed cell death, contributes to the development of lung injury. Protectin conjugates in tissue regeneration 1 (PCTR1) is an endogenous lipid mediator that exerts protective effects against multiorgan injury. However, the role of PCTR1 in the ferroptosis of sepsis-related ALI remains unknown. Methods A pulmonary epithelial cell line and a mouse model of ALI stimulated with lipopolysaccharide (LPS) were established in vitro and in vivo. Ferroptosis biomarkers, including ferrous (Fe2+), glutathione (GSH), malondialdehyde (MDA) and 4-Hydroxynonenal (4-HNE), were assessed by relevant assay kits. Glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) protein levels were determined by western blotting. Lipid peroxides were examined by fluorescence microscopy and flow cytometry. Cell viability was determined by a CCK-8 assay kit. The ultrastructure of mitochondria was observed with transmission electron microscopy. Morphology and inflammatory cytokine levels predicted the severity of lung injury. Afterward, related inhibitors were used to explore the potential mechanism by which PCTR1 regulates ferroptosis. Results PCTR1 treatment protected mice from LPS-induced lung injury, which was consistent with the effect of the ferroptosis inhibitor ferrostatin-1. PCTR1 treatment decreased Fe2+, PTGS2 and lipid reactive oxygen species (ROS) contents, increased GSH and GPX4 levels and ameliorated mitochondrial ultrastructural injury. Administration of LPS or the ferroptosis agonist RSL3 resulted in reduced cell viability, which was rescued by PCTR1. Mechanistically, inhibition of the PCTR1 receptor lipoxin A4 (ALX), protein kinase A (PKA) and transcription factor cAMP-response element binding protein (CREB) partly decreased PCTR1 upregulated GPX4 expression and a CREB inhibitor blocked the effects ofPCTR1 on ferroptosis inhibition and lung protection. Conclusion This study suggests that PCTR1 suppresses LPS-induced ferroptosis via the ALX/PKA/CREB signaling pathway, which may offer promising therapeutic prospects in sepsis-related ALI.

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“…It was found that Gln treatment increased the ratio of cell cycle G1 of ISCs and promoted the transcription levels of cyclin CDK1/CDK2/CDK4 in our research. Cyclin D1 is a key factor in the proliferation of ISCs and is a target of the Hippo-YAP signal [ 31 ]. This study found that the supplementation of Gln promoted the expression of protein Cyclin D1 and improved ISCs proliferation after burns.…”

Section: Discussionmentioning

confidence: 99%

Potential Effect of Glutamine in the Improvement of Intestinal Stem Cell Proliferation and the Alleviation of Burn-Induced Intestinal Injury via Activating YAP: A Preliminary Study

Chen

Zhang

et al. 2023

Nutrients

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Burn injury is a common form of traumatic injury that leads to high mortality worldwide. A severe burn injury usually induces gut barrier dysfunction, partially resulting from the impairment in the proliferation and self-renewal of intestinal stem cells (ISCs) post burns. As a main energy substance of small intestinal enterocytes, glutamine (Gln) is important for intestinal cell viability and growth, while its roles in ISCs-induced regeneration after burns are still unclear. To demonstrate the potential effects of Gln in improving ISCs proliferation and alleviating burn-induced intestinal injury, in this study, we verified that Gln significantly alleviated small intestine injury in burned mice model. It showed that Gln could significantly decrease the ferroptosis of crypt cells in the ileum, promote the proliferation of ISCs, and repair the crypt. These effects of Gln were also confirmed in the mouse small intestine organoids model. Further research found that Yes-associated protein (YAP) is suppressed after burn injury, and Gln could improve cell proliferation and accelerate the renewal of the damaged intestinal mucosal barrier after burns by activating YAP. YAP is closely associated with the changes in intestinal stem cell proliferation after burn injury and could be served as a potential target for severe burns.

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YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis

Cited by 29 publications

References 45 publications

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage

Protectin conjugates in tissue regeneration 1 alleviates sepsis-induced acute lung injury by inhibiting ferroptosis

Potential Effect of Glutamine in the Improvement of Intestinal Stem Cell Proliferation and the Alleviation of Burn-Induced Intestinal Injury via Activating YAP: A Preliminary Study

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