SLC7A11-associated astrocyte states are linked to redox imbalance and synaptic microenvironment remodeling in multiple sclerosis: translational implications

Vollständiger Abstract

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Abstract Background Multiple sclerosis (MS) is characterized by inflammatory demyelination, oxidative stress, and neurological dysfunction. Despite disease-modifying therapies, chronic active lesions and ongoing neurodegeneration remain largely untreated, highlighting the need for mechanistically informed translational targets. Methods We analyzed a human single-nucleus RNA-sequencing dataset (GSE279180) including healthy controls and MS samples. Astrocyte subpopulations were examined using reclustering, pseudotime inference, co-expression network analysis, SLC7A11-high/low stratification, virtual knockout prediction, and gene set enrichment analysis. Key findings were further assessed in vivo using a cuprizone-induced demyelination mouse model. Results Broad cellular remodeling was observed in MS lesions, including altered neuroactive ligand-receptor interactions, calcium signaling, glutamatergic synapse, and synaptic vesicle cycle-related pathways. SLC7A11 was enriched in astrocytes and increased along later pseudotime stages. SLC7A11-high astrocytes were linked to impaired antioxidant defense (GSH/GPX4) and synaptic vesicle-related remodeling. CPZ-treated mice showed decreased SLC7A11/GPX4 colocalization and increased SYP–GFAP colocalization, along with behavioral deficits, demyelination, and inflammatory-redox imbalance. Conclusions SLC7A11-associated astrocyte states are associated with redox imbalance and synaptic microenvironment remodeling in MS. These states may inform future biomarker development and therapeutic investigation. Our findings provide a glial-state framework linking neuroinflammation, oxidative stress, and synaptic dysfunction, highlighting potential avenues for translational strategies in MS.