ArticleCell death and differentiation2025
GSDME-mediated pyroptosis in microglia exacerbates demyelination and neuroinflammation in multiple sclerosis: insights from humans and cuprizone-induced demyelination model mice.
Article in Cell death and differentiation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Cuproptosis: an emerging member of the immunogenic cell death family.Cell death and differentiation · 2026Article
- Gasdermin E: Bridging Pyroptosis, Immunity, and Disease Pathogenesis Toward Precision Intervention.The protein journal · 2026Review
- The landscape of regulated cell death: It's all downhill from here.Molecular cell · 2026Review
- HSP60 Mediates NLRP3 Inflammasome-Dependent Microglial Pyroptosis Via the TLR4/MyD88/NF-κB Signaling Axis After Subarachnoid Hemorrhage.Inflammation · 2026Article
- Smoldering neuroinflammation in progressive multiple sclerosis: mechanisms, imaging biomarkers, and therapeutic opportunities.Frontiers in immunology · 2026Review
- A-to-I RNA editing profiles and distinct immune responses in myelin oligodendrocyte glycoprotein antibody-positive optic neuritis.Frontiers in immunology · 2026Article
- Gasdermins in neurodegeneration: emerging mechanisms and therapeutic targets.Cell death & disease · 2025Review
- Advances in Therapeutics Research for Demyelinating Diseases.Pharmaceuticals (Basel, Switzerland) · 2025Review
- SARS-CoV-2 N protein exerts antitumor effects in NSCLC by inducing DNA damage and augmenting chemotherapeutic sensitivity.Medical oncology (Northwood, London, England) · 2025Article
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Authors and funding
14 authors.
Funding
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Abstract
Demyelination, a hallmark of multiple sclerosis (MS), disrupts neural conduction due to myelin sheath degradation. Microglia-mediated inflammation plays a pivotal role in this process, with emerging evidence implicating gasdermin E (GSDME) in neuroinflammation and neurodegeneration. However, the specific role of GSDME in MS remains unclear. Here, we investigated the involvement of GSDME in MS using brain tissues from MS patients and cuprizone (CPZ)-induced demyelination model mice. We observed elevated GSDME expression in the central nervous system (CNS) lesions of MS patients, with pronounced GSDME cleavage in microglia at injury sites. Genetic knockout of Gsdme alleviated CPZ-induced motor deficits, demyelination, and neuroinflammation. Furthermore, caspase-3 inhibition significantly suppressed GSDME activation, resulting in reduced demyelination, motor coordination impairment, and neuroinflammation. In an experimental autoimmune encephalomyelitis (EAE) model, caspase-3/GSDME-mediated microglial pyroptosis critically mediated the progression of neuroinflammation and white matter demyelination. Transcriptome sequencing revealed that GSDME regulated the expression of genes related to disease-associated microglia (DAMs) and impaired microglial autophagy, a process critical for myelin debris clearance. Gsdme knockout downregulated the expression of genes associated with DAMs and CPZ-induced microglia-driven demyelination while increasing the expression of remyelination-related genes (Cybb and Cd74). In vitro, GSDME suppression promoted microglial autophagy and myelin debris clearance. Collectively, our findings highlight GSDME-mediated pyroptosis as a key driver of demyelination and neuroinflammation in MS, suggesting novel therapeutic targets for neuroinflammatory disorders.
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