Ferroptosis as an emerging target in inflammatory diseases

Mao, Huimin; Zhao, Yunhe; Li, Houxuan; Lei, Lang

doi:10.1016/j.pbiomolbio.2020.04.001

Cited by 122 publications

(115 citation statements)

References 89 publications

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“…Ferritinophagy has long been recognized a hallmark of ferroptosis, a newly‐characterized regulated cell death 28 . Degradation of ferritin releases large quantities of free iron into the labile iron pool, which can trigger excessive intracellular ROS, exhaust pool of cytosolic glutathione, and promote lipid peroxidation 5 .…”

Section: Discussionmentioning

confidence: 99%

NCOA4‐mediated ferritinophagy promoted inflammatory responses in periodontitis

Guo

Zhao

et al. 2021

J of Periodontal Research

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Background/Objectives Iron homeostasis plays a crucial role in the combat against pathogen invasion. Ferrous iron can trigger generous production of reactive oxygen species (ROS) by Fenton reaction. Nuclear receptor coactivator 4 (NCOA4), a selective cargo receptor to deliver ferritin to lysosome, may trigger release of ferritin‐bound iron into the cytosol. The aim of the present study was to explore whether NCOA4‐mediated ferritinophagy participated in the pathogenesis of periodontitis, and its role in promoting the periodontal inflammation. Methods Inflamed and healthy periodontal tissues were harvested for immunobiological staining of ferritinophagy‐related genes in the periodontal tissues, while real‐time quantitative PCR (qPCR) was utilized to detect mRNA transcription. Periodontal ligament fibroblasts (PDLFs) were isolated and infected with Porphyromonas gingivalis. The mRNA transcription and protein expression of genes involved in the iron metabolism, including NCOA4, transferrin receptor 1 (TFR1), and ferroportin (SLC40A1) were detected by qPCR and western blot. Levels of labile iron pool and ROS production were detected by flow cytometry and confocal endoscopy. Small interference RNA was utilized to knock down NCOA4. Results Elevated expression of NCOA4, ferritin heavy chain, and light chain were observed in the diseased periodontal tissues. P. gingivalis infection promoted expression of TFR1, NCOA4, and microtubule‐associated protein 1‐light chain 3 B (LC3B), enhanced levels of intracellular labile iron pool and ROS production. NCOA4 knockdown reduced ROS generation in PDLFs in response to P. gingivalis and mitigated production of pro‐inflammatory monocyte chemoattractant protein‐1 and interleukin 6. P. gingivalis triggered activation of c‐Jun N‐terminal kinase (JNK) and p38 mitogen‐activated protein kinase signaling pathway. In addition, inhibitors of JNK, SP600125, and inhibitors of p38, SB203580 blocked NCOA4 transcription. Conclusion NCOA4‐ferritinophagy participated in the progress of periodontitis progression. P. gingvalis‐triggered ferritinophagy aggravated production of ROS and inflammatory responses in PDLFS. These findings suggest iron homeostasis plays an important role in the pathogenesis of periodontitis.

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Section: Discussionmentioning

confidence: 99%

NCOA4‐mediated ferritinophagy promoted inflammatory responses in periodontitis

Guo

Zhao

et al. 2021

J of Periodontal Research

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“…Although NCOA4-mediated ferritinophagy has been implicated in chronic obstructive pulmonary disease, stroke, and ischemia-reperfusion injuries 21 , the molecular mechanisms modulating ferritinophagy and ferroptosis remain obscure. The cigarette smoke induced ferroptosis in bronchial epithelial cells 19,27 and vascular smooth muscle cells 28 , and NCOA4-mediated ferritinophagy promoted ROS accumulation in epithelial cells 27 .…”

Section: Discussionmentioning

confidence: 99%

“…Ferroptosis is a ROS-dependent cell death, and lipid peroxidation by excessive intracellular ROS plays a crucial role in its onset 21 ; we then investigated whether butyrate induce excessive ROS generation in PDLFs. Long-term treatment with butyrate significantly reduced the level of GSH, which can be utilized by GPX4 as electron donors to reduce the intracellular ROS ( Fig.…”

Section: Butyrate-induced Ros Production and Lipid Peroxidationmentioning

confidence: 99%

Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy

Zhao

Guo

et al. 2020

Cell Death Discov.

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Loss of periodontal ligament fibroblasts (PDLFs) is one critical issue for regenerating lost periodontal tissues. A wide variety of regulated cell death pathways, such as apoptosis, pyroptosis, and necroptosis have been proposed in the periodontitis development. The aim of the present study was to explore whether long-term periodontitis-level butyrate may trigger ferroptosis, a newly characterized iron-dependent regulated cell death in PDLFs. Here, we showed that long-term treatment of butyrate, an important short-chain fatty acid in the periodontal pocket, induces the cargo receptor nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis in PDLFs. Butyrate-induced iron accumulation, reactive oxygen species (ROS) generation, glutathione depletion and lipid peroxidation in PDLFs, and the butyrate-induced ferroptosis can be blocked by the lipid peroxide scavenger ferrostatin-1. The NCOA4-mediated ferritinophagy is dependent on p38/hypoxia inducible factor-1α (HIF-1α) pathway activation as well as Bromodomain-containing protein (BRD) 4 and cyclin-dependent kinase 9 (CDK9) coordination. These lines of evidence provide a new mechanistic insight into the mechanism of loss of PDLFs during periodontitis development, showing that periodontitis-level butyrate disrupted iron homeostasis by activation of NCOA4-mediated ferritinophagy, leading to ferroptosis in PDLFs.

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“…There are some in ammatory factors related to the metabolism of peroxides and arachidonic acid in ferroptosis tissues(18). Studies have shown that both ferroptosis and in ammatory diseases have the depletion of Gx4 and GSH, the increase of lipid peroxidation products, and the interruption of iron metabolism (19). At present, although a variety of molecular mechanisms and signaling pathways can lead to ferroptosis, Iron metabolism and lipid peroxidation signaling are the main way to regulate ferroptosis (20).…”

Section: Discussionmentioning

confidence: 99%

Effects of Gastrodin on Analgesia and Inhibition of Ferroptosis

Wang

Liu

et al. 2021

Preprint

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Background: Gastrodin possesses low toxicity and a broad range of pharmacological activities and exhibits beneficial effects in neurological diseases. This study investigated the effects of gastrodin (GAS) on analgesic, anti-inflammatory, anxiolytic and inhibition of ferroptosis. Materials and Methods: The chronic inflammatory pain model of C57BL/6J mice was established by hindpaw injection of complete Freund’s adjuvant (CFA). After GAS treatment, Thermal hyperalgesia test, Mechanical allodynia test, Elevated plus-maze (EPMT) and Open-field test (OFT) were performed to assess the behavioral changes of pain and anxiety. mRNAs of FTHI, GPX4, HO-1 and PTGS2 were measured by RT-qPCR. Results: In CFA-injected C57BL/6 mice, we found that the mechanical and thermal pain threshold was increased with treatment of GAS. In EPMT, the number of entries in open arms and retention times of open arms were increased by GAS. In the OFT, the time spent in the central area was also increased. Furthermore, GAS enhanced mRNA expressions of FTHI, GPX4 and H0-1, as well as decreased the expression of PTGS2 in a dose-dependent manner. Conclusion: GAS is effective in the treatment of mice chronic inflammatory pain and anxiety-like behaviors. It maybe exhibit potential neuroprotective effects through inhibition of ferroptosis.

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Ferroptosis as an emerging target in inflammatory diseases

Cited by 122 publications

References 89 publications

NCOA4‐mediated ferritinophagy promoted inflammatory responses in periodontitis

NCOA4‐mediated ferritinophagy promoted inflammatory responses in periodontitis

Periodontitis-level butyrate-induced ferroptosis in periodontal ligament fibroblasts by activation of ferritinophagy

Effects of Gastrodin on Analgesia and Inhibition of Ferroptosis

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