H1N1 influenza virus infection through NRF2-KEAP1-GCLC pathway induces ferroptosis in nasal mucosal epithelial cells

Liu, Chengcheng; Wu, Xinhao; Bing, Xin; Qi, Wenwen; Zhu, Fulong; Guo, Na; Li, Chengzhilin; Gao, Xiaohuan; Cao, Xue; Zhao, Mingqiu; Xia, Ming

doi:10.1016/j.freeradbiomed.2023.05.004

Cited by 9 publications

(5 citation statements)

References 42 publications

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“…Herpes simplex virus-1 (HSV-1) promotes KEAP1-dependent ubiquitination and degradation of NRF2 to induce ferroptosis and inflammation in human astrocytes (U373) and microglia (HMC3) cells [ 58 ]. Newcastle disease virus [ 31 ], H3N2 swine influenza virus, and H1N1 influenza virus infection [ 59 , 60 ] can cause ferroptosis, which is characterized mainly by the accumulation of ferrous ions, ROS, and MDA and a decreased GSH level. Here, we found that H5N1 HPAIV infection increased the levels of ROS, MDA, and ferrous ions and reduced mitochondrial membrane potential and GSH levels.…”

Section: Discussionmentioning

confidence: 99%

TRIM21 Promotes Oxidative Stress and Ferroptosis through the SQSTM1-NRF2-KEAP1 Axis to Increase the Titers of H5N1 Highly Pathogenic Avian Influenza Virus

Wei,

Gu,

Zhou

et al. 2024

IJMS

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Tripartite motif-containing protein 21 (TRIM21) is involved in signal transduction and antiviral responses through the ubiquitination of protein targets. TRIM21 was reported to be related to the imbalance of host cell homeostasis caused by viral infection. Our studies indicated that H5N1 highly pathogenic avian influenza virus (HPAIV) infection up-regulated TRIM21 expression in A549 cells. Western blot and qPCR results showed that knockdown of TRIM21 alleviated oxidative stress and ferroptosis induced by H5N1 HPAIV and promoted the activation of antioxidant pathways. Co-IP results showed that TRIM21 promoted oxidative stress and ferroptosis by regulating the SQSTM1-NRF2-KEAP1 axis by increasing SQSTM1 K63-linked polyubiquitination under the condition of HPAIV infection. In addition, TRIM21 attenuated the inhibitory effect of antioxidant NAC on HPAIV titers and enhanced the promoting effect of ferroptosis agonist Erastin on HPAIV titers. Our findings provide new insight into the role of TRIM21 in oxidative stress and ferroptosis induced by viral infection.

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Section: Discussionmentioning

confidence: 99%

TRIM21 Promotes Oxidative Stress and Ferroptosis through the SQSTM1-NRF2-KEAP1 Axis to Increase the Titers of H5N1 Highly Pathogenic Avian Influenza Virus

Wei,

Gu,

Zhou

et al. 2024

IJMS

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“…Combined with ARE, Nrf2 inhibits the expression of type II cytokines in airway epithelial cells, inhibits oxidative stress, and slows the symptoms and signs of asthma ( 97 ). Nrf2-Keap1 signaling not only resists oxidative effects in asthma, but also promotes the expression of systemic Xc- and GPX4 factors, regulates SLC7A11 activity, reduces ROS production, and ultimately inhibits ferroptosis ( 98 ). Recent studies have found that licorice can activate the activity of Nrf2 and play a protective role in airway altitude sickness, providing new ideas for the clinical treatment of asthma ( 99 ).…”

Section: Ferroptosis In Pulmonary Diseasementioning

confidence: 99%

A deep insight into ferroptosis in lung disease: facts and perspectives

Zhang,

Xiang,

et al. 2024

Front. Oncol.

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In the last decade, ferroptosis has received much attention from the scientific research community. It differs from other modes of cell death at the morphological, biochemical, and genetic levels. Ferroptosis is mainly characterized by non-apoptotic iron-dependent cell death caused by iron-dependent lipid peroxide excess and is accompanied by abnormal iron metabolism and oxidative stress. In recent years, more and more studies have shown that ferroptosis is closely related to the occurrence and development of lung diseases. COPD, asthma, lung injury, lung fibrosis, lung cancer, lung infection and other respiratory diseases have become the third most common chronic diseases worldwide, bringing serious economic and psychological burden to people around the world. However, the exact mechanism by which ferroptosis is involved in the development and progression of lung diseases has not been fully revealed. In this manuscript, we describe the mechanism of ferroptosis, targeting of ferroptosis related signaling pathways and proteins, summarize the relationship between ferroptosis and respiratory diseases, and explore the intervention and targeted therapy of ferroptosis for respiratory diseases.

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“…Xu et al found that HSV-1 enhances the action of Keap1 on Nrf2 to promote Nrf2's ubiquitination and degradation, leading to reduction in the gene expression of antioxidant stress, which disrupts cellular homeostasis and promotes ferroptosis [144]. Liu et al found that Nrf2 expression was significantly reduced during H1N1 infection and induced ferroptosis in human nasal epithelial progenitor cells (hNECs) through elevated intracellular oxidative levels caused by the NRF2-KEAP1-GCLC axis, resulting in nasal mucosal epithelial inflammation [145].…”

Section: Virus Targeting Keap1-nrf2 Axis Affects Downstream Gpx4 Acti...mentioning

confidence: 99%

Molecular Mechanisms of Ferroptosis and Its Role in Viral Pathogenesis

Huang,

Wu,

et al. 2023

Viruses

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Ferroptosis is a novelty form of regulated cell death, and it is mainly characterized by iron accumulation and lipid peroxidation in the cells. Its underlying mechanism is related to the amino acid, iron, and lipid metabolisms. During viral infection, pathogenic microorganisms have evolved to interfere with ferroptosis, and ferroptosis is often manipulated by viruses to regulate host cell servicing for viral reproduction. Therefore, this review provides a comprehensive overview of the mechanisms underlying ferroptosis, elucidates the intricate signaling pathways involved, and explores the pivotal role of ferroptosis in the pathogenesis of viral infections. By enhancing our understanding of ferroptosis, novel therapeutic strategies can be devised to effectively prevent and treat diseases associated with this process. Furthermore, unraveling the developmental mechanisms through which viral infections exploit ferroptosis will facilitate development of innovative antiviral agents.

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H1N1 influenza virus infection through NRF2-KEAP1-GCLC pathway induces ferroptosis in nasal mucosal epithelial cells

Cited by 9 publications

References 42 publications

TRIM21 Promotes Oxidative Stress and Ferroptosis through the SQSTM1-NRF2-KEAP1 Axis to Increase the Titers of H5N1 Highly Pathogenic Avian Influenza Virus

TRIM21 Promotes Oxidative Stress and Ferroptosis through the SQSTM1-NRF2-KEAP1 Axis to Increase the Titers of H5N1 Highly Pathogenic Avian Influenza Virus

A deep insight into ferroptosis in lung disease: facts and perspectives

Molecular Mechanisms of Ferroptosis and Its Role in Viral Pathogenesis

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