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Pseudorabies Virus Triggers Ferritinophagy-Mediated Ferroptosis and Neuroinflammation in Viral Encephalitis

ABSTRACT:

Pseudorabies virus (PRV), a member of the Alphaherpesvirinae subfamily, primarily infects pigs and poses a significant threat to the swine industry. In recent years, emerging PRV variants have been reported to infect humans, predominantly causing encephalitis. Ferroptosis is a recently identified form of programmed cell death, characterized by iron-dependent lipid peroxidation. It has been implicated in the pathogenesis of various diseases, including neurodegenerative disorders and viral infections. However, whether PRV induces ferroptosis in the central nervous system (CNS) and the underlying mechanisms remain fully elucidated. This study demonstrates that PRV infection induces ferroptosis in N2a cells and murine brains. Specifically, PRV infection triggers ferritinophagy in N2a cells and brain, increasing intracellular free iron levels and subsequent lipid peroxidation, ultimately driving ferroptosis. Furthermore, PRV-induced ferroptosis is closely associated with neuroinflammation. Mechanistically, ferroptosis upregulates prostaglandin-endoperoxide synthase 2 (PTGS2), thereby enhancing prostaglandin E2 (PGE2) synthesis and exacerbating inflammatory responses. Integrated transcriptomic and metabolomic analyses further confirm that PRV-induced ferroptosis drives neuroinflammation through the PTGS2/PGE2 pathway. Notably, treatment with the ferroptosis inhibitor deferoxamine (DFO) effectively mitigates PRV-induced ferroptosis, reduces viral titers in mouse brains, and alleviates viral encephalitis. In conclusion, our study reveals the critical role of ferroptosis in PRV-induced viral encephalitis, providing new therapeutic insights for treating PRV-associated neurological diseases.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS12373 | MetaboLights | 2026-04-17

REPOSITORIES: MetaboLights

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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.

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Pseudorabies Virus Triggers Ferritinophagy-Mediated Ferroptosis and Neuroinflammation in Viral Encephalitis

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