Apolipoprotein E in spinal cord injury: mechanisms of lipid dysregulation, neuroinflammation, and opportunities for repair.

Traumatic spinal cord injury (SCI) is a devastating condition that affects millions of people worldwide and remains without effective pharmacological therapies that substantially improve neurological recovery. A major barrier to repair is the persistent secondary neuroinflammatory response that evolves over weeks to months after injury. Although neuroinflammation represents an attractive therapeutic target, broadly acting immunosuppressive approaches have yielded limited clinical benefit, highlighting the need to identify mechanisms that drive detrimental inflammation while preserving beneficial immune functions that support repair. Emerging evidence identifies dysregulated lipid handling as one such mechanism. SCI generates a substantial lipid burden through myelin and cellular breakdown, while lipidomic and metabolomic studies reveal persistent, dynamic alterations in lipid processing, storage, and transport. The capacity of resident glia and infiltrating immune cells to manage this lipid burden has important consequences for inflammatory state and tissue repair. Apolipoprotein E (ApoE), a major regulator of lipid transport and redistribution in the central nervous system, lies at the intersection of these processes, linking lipid metabolism with neuroinflammation and recovery after SCI. Here, we critically evaluate ApoE biology and its relationship to lipid dysregulation after SCI, together with preclinical evidence targeting ApoE-associated and broader lipid-regulatory pathways, including ApoE mimetics, LXR/RXR and PPARγ signaling, and statins. We distinguish demonstrated therapeutic mechanisms from proposed ApoE-dependent effects and evaluate emerging clinical evidence for lipid-modifying interventions in SCI. Finally, we consider key barriers to translation, including injury heterogeneity, sex, age and ApoE genotype, therapeutic timing and delivery, and the integration of lipid-directed interventions into multimodal strategies for SCI repair. Together, current evidence positions lipid dysregulation as an important and potentially tractable component of SCI pathogenesis, while defining the studies needed to establish the contribution of ApoE-directed and broader lipid-modifying strategies to neurological repair.