Dataset Information

Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis

ABSTRACT: Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. However, the lack of effective and safe clinical precautionary measure is still the main problem in preventing hepatic ferroptosis. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis. Therefore, we provide mechanistic evidence for the IFN-stimulated DHX58 in promoting the translation of m6A-modified Gpx4 mRNA, and suggest the promising clinical potential of IFN-α pre-treatment in the prevention of hepatic ferroptosis.

INSTRUMENT(S): timsTOF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Jia Kaiwei

LAB HEAD: Kaiwei jia

PROVIDER: PXD042083 | Pride | 2024-05-24

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	RD168LQ_LGP2_KO1_Slot1-7_1_7422.d.zip	Other
	RD168LQ_LGP2_KO2_Slot1-8_1_7423.d.zip	Other
	RD168LQ_LGP2_KO3_Slot1-9_1_7424.d.zip	Other
	RD168LQ_NC1_Slot1-4_1_7418.d.zip	Other
	RD168LQ_NC2_Slot1-5_1_7419.d.zip	Other

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Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis.

Jia Kai-Wei KW Yao Ren-Qi RQ Fan Yi-Wen YW Zhang Ding-Ji DJ Zhou Ye Y Wang Min-Jun MJ Zhang Li-Yuan LY Dong Yue Y Li Zhi-Xuan ZX Wang Su-Yuan SY Wang Mu M Li Yun-Hui YH Zhang Lu-Xin LX Lei Ting T Gui Liang-Chen LC Lu Shan S Yang Ying-Yun YY Wang Si-Xian SX Yu Yi-Zhi YZ Yao Yong-Ming YM Hou Jin J

Military Medical Research 20240415 1

<h4>Background</h4>Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family.<h4>Methods</h4>The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome an ...[more]

PMID: 38622688

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Project description:Numerous neurological diseases involve neuroinflammation, a process in which immune cells, particularly microglia, contribute to neuronal death. Ferroptosis, a recently identified form of regulated cell death, is implicated in various diseases characterized by neuronal injury. Nicotinamide mononucleotide (NMN), a potent NAD+ precursor supplement, has been found to inhibit neuroinflammation and ferroptosis. However, the mechanisms of NMN in both ferroptosis and neuroinflammation remains unclear. The present study aimed to investigate the impact of NMN on neuroinflammation and the susceptibility of microglia to ferroptosis. Ferroptosis markers in microglia exposed to lipopolysaccharide (LPS) were analyzed using CCK8, flow cytometry, ELISA, and RT-qPCR. The effects of NMN on LPS-induced ferroptosis in microglia were evaluated through flow cytometry, western blotting, and immunofluorescence staining. RT-qPCR analysis assessed the inflammatory cytokine production of microglia subjected to ferrostatin-1-regulated ferroptosis. RNA sequencing elucidated the underlying mechanisms of NMN-associated microglia ferroptosis under LPS induction. In BV2 microglia, an inhibitor of Glutathione Peroxidase 4(GPX4), RSL3, was employed to suppress GPX4 expression. Intracerebroventricular injection of LPS was performed to evaluate neuroinflammation and microglia activation in vivo. LPS treatment resulted in decreased cell viability, accompanied by upregulation of ferroptosis markers SLC7A11 and GPX4, and elevated levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and total iron in a dose-dependent manner. NMN effectively rescued LPS-induced ferroptosis and improved cell viability in microglia. Co-administration of NMN and ferrostatin-1 significantly reduced proinflammatory cytokine production in microglia following the introduction of LPS stimuli. Mechanistically, NMN facilitated glutathione (GSH) production, and promoted resistance to lipid peroxidation in a GPX4-dependent manner, repressing cytokine transcription and protecting cells from ferroptosis. RNA sequencing elucidated the underlying mechanism of NMN-associated microglia ferroptosis under LPS induction. Furthermore, simultaneous injection of NMN ameliorated LPS-induced ferroptosis and neuroinflammation in mouse brains. The data from the present study indicated that NMN enhances GPX4-mediated ferroptosis defense against LPS-induced ferroptosis in microglia by recruiting GSH, thereby inhibiting neuroinflammation. Therefore, therapeutic approaches targeting ferroptosis in diseases using NMN should consider both its anti-ferroptosis and anti-inflammatory effects to achieve optimal outcomes, presenting promising strategies for treating neuroinflammation-related diseases or disorders.