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Glycosylation Inhibition as a Therapeutic Strategy for Neuroinflammatory Disorders: The Potential of Tanshinone IIA;BV2 cell data

ABSTRACT: our study employed a combined proteomic and glycoproteomic approach to investigate the role of protein glycosylation in lipopolysaccharide (LPS)-induced neuroinflammation models. Bioinformatics analysis of the proteomic and glycoproteomic data further emphasized a strong connection between our observed changes and pathways implicated in glycosylation and neuroinflammation. Our findings revealed an overall increase in protein glycosylation levels during neuroinflammatory processes. Crucially, we demonstrated that the pan-glycosylation inhibitor NGI-1 effectively suppressed the inflammatory response in BV2 microglia cells. Building on these findings and leveraging the proteomic and glycoproteomic data from LPS-induced models, we subsequently screened Tanshinone IIA (STS), a bioactive component of Salvia miltiorrhiza (Danshen), identifying it as a potent therapeutic candidate for neuroinflammatory disorders. Tanshinone IIA effectively attenuated aberrant protein glycosylation by reducing glycan occupancy. Mechanistically, this modulatory effect likely involves influencing UDP-GlcNAc levels within the glycosylation biosynthesis pathway and impacting N-acetylaspartate metabolism, thereby disrupting aberrant protein glycosylation and consequently alleviating the inflammatory response. Collectively, our findings offer novel insights into the therapeutic potential of targeting glycosylation modifications in neuroinflammation.

ORGANISM(S): Mus Musculus

SUBMITTER: Dezhi Kong

PROVIDER: PXD066194 | iProX | Wed Jul 16 00:00:00 BST 2025

REPOSITORIES: iProX

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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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Glycosylation Inhibition as a Therapeutic Strategy for Neuroinflammatory Disorders: The Potential of Tanshinone IIA;BV2 cell data

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