ABCA1-mediated lipid efflux restrains oxidative stress and neuroinflammation after spinal cord injury

Spinal cord injury (SCI) triggers a persistent inflammatory microenvironment that contributes to secondary tissue damage and neurological dysfunction. However, the metabolic mechanisms sustaining activation of lesion-associated phagocytes remain incompletely understood. Here, we identify lipid-laden microglia/macrophages as a metabolically stressed inflammatory state that emerges after SCI and investigate the role of lipid efflux in regulating this process. Single-nucleus and immune-enriched transcriptomic analyses revealed coordinated upregulation of cholesterol transport and inflammatory pathways in lesion-associated phagocytes. Among lipid transporters, the ATP-binding cassette transporter ABCA1 was consistently induced across post-injury stages. Conditional deletion of ABCA1 in Cx3cr1-lineage cells led to excessive lipid droplet accumulation, enhanced reactive oxygen species production, sustained pro-inflammatory cytokine expression, and impaired locomotor recovery following SCI. To therapeutically target this pathway, we performed structure-guided virtual screening and identified the small molecule Z231 as an ABCA1-binding compound. Pharmacological activation of ABCA1 reduced lipid accumulation, suppressed oxidative stress and inflammatory gene expression, and partially restored mitochondrial metabolic balance in microglia exposed to myelin debris. In vivo, systemic Z231 administration attenuated inflammatory signaling and improved functional recovery after SCI. Together, these findings identify ABCA1-mediated lipid efflux as a key regulator of microglial metabolic stress and neuroinflammation after spinal cord injury, and suggest that targeting lipid handling pathways may represent a potential therapeutic strategy for SCI.