CD300f is required for efficient lipid handling during cuprizone-induced demyelination

Microglia play a crucial role in central nervous system homeostasis and response to demyelination, yet the mechanisms that coordinate the sensing and processing of myelin-derived lipids remain poorly understood. CD300f is a lipid-sensing innate immune receptor expressed by myeloid cells that has been implicated in tissue damage sensing, phagocytosis, and lipid metabolism. Here, we investigated the role of CD300f in the cuprizone-induced demyelination model. Using CD300f-deficient mice, we demonstrate exacerbated demyelination, increased lipid droplet accumulation, impaired microglial responses, and reduced remyelination accompanied by motor coordination deficits. Bulk RNA sequencing of the corpus callosum at the peak of demyelination revealed enrichment of homeostatic, disease-associated (DAM), and foamy microglial signatures, together with increased expression of genes involved in lysosomal function, phagocytosis, inflammation, and lipid metabolism. Notably, these transcriptional changes were associated with marked lipid droplet accumulation in microglia and enrichment of microglial states previously linked to chronic demyelinating lesions. These findings suggest that CD300f is required for efficient handling of myelin-derived lipids and for microglial metabolic adaptation during demyelination. Our study identifies CD300f as a critical regulator of microglial function and lipid homeostasis and highlights this receptor as a potential therapeutic target in demyelinating diseases.