Cognitive impairment is a common manifestation of central neuropsychiatric systemic lupus erythematosus (cNPSLE), yet its underlying pathological basis remains elusive. This study aims to clarify the relationship between white matter demyelination and cognitive decline in cNPSLE, characterize the phenotypic transformation of oligodendrocytes within the inflammatory microenvironment, and investigate the regulatory role of complement signaling in this process.

Brain MRI and diffusion tensor imaging (DTI) were performed on cNPSLE patients, with white matter structural integrity correlated to Montreal Cognitive Assessment (MoCA) scores. A pristane-induced lupus (PIL) mouse model was employed to evaluate demyelination and cognitive deficits via immunofluorescence, electron microscopy, and behavioral assays. Single-cell RNA sequencing (scRNA-seq) was utilized to analyze the lineage dynamics and transcriptional profiles of oligodendrocytes. Complement sources and targets were identified using proteomics and in vitro assays, and the key molecular mechanisms were validated using siRNA interference and conditional knockout (cKO) mice.

Clinical data revealed that the severity of white matter injury in cNPSLE patients significantly correlated with the degree of cognitive decline. The PIL mouse model successfully replicated corpus callosum demyelination and cognitive deficits. scRNA-seq demonstrated significant transcriptional reprogramming of oligodendrocytes, shifting from a mature myelinating phenotype toward an immune-oligodendrocyte (Im-OL) phenotype, characterized by upregulated inflammatory pathways and impaired myelination capacity. Mechanistically, astrocytes were identified as the primary local source of C1q, which accumulates in the corpus callosum and binds to the C1qbp receptor on oligodendrocytes. This interaction activates the MAPK/NF-κB signaling pathway to drive Im-OL formation. In vitro knockdown of C1qbp blocked this inflammatory signaling. In vivo studies further confirmed that exogenous C1q induces demyelination and cognitive impairment, whereas specific deletion of C1qbp in oligodendrocyte precursor cells (OPCs) significantly reversed these pathological changes.

This study identifies a novel neuroimmune mechanism in cNPSLE, where astrocyte-derived C1q drives the transformation of oligodendrocytes into an immune phenotype via C1qbp, leading to corpus callosum demyelination and cognitive dysfunction. The C1q–C1qbp axis plays a critical role in this process, suggesting its potential as a therapeutic target for intervening in white matter injury and cognitive impairment in cNPSLE.