Regulating PPARG Reduces Lipid Accumulation in Microglia and Promotes Functional Recovery After Spinal Cord Injury

Macrophages infiltrate the spinal cord post‐injury, decreasing over time. Microglia phagocytose myelin debris, increasing lipid accumulation. Macrophage deletion improves outcomes, while microglial deletion worsens them. The LD+ microglia subtype shows abnormal Pparg signaling. PPARG promotes lipid metabolism and recovery, and atorvastatin reverses altered metabolic processes. Targeting PPARG and its agonists offers a promising therapeutic approach for spinal cord injury. Abstract Spinal cord injury (SCI) substantially affects functional capacity and the immune system plays a crucial role in recovery. Examining alterations in microglia metabolism can lead to improved repair mechanisms; however, the molecular subtyping of microglia lacks consensus. In this study, the effects of SCI on macrophages and microglia in mice are investigated to identify tailored therapeutic targets and interventions for patients with SCI. Macrophages infiltrate the spinal cord shortly after injury; however, infiltration decreases over time. Microglial phagocytosis of myelin debris is associated with increased lipid accumulation. Macrophage deletion improves outcomes, whereas microglial deletion worsens them. The PLIN2+ microglia subtype in lipid droplet formation shows abnormal activation of the Pparg signaling pathway compared with that with other subtypes. PPARG promotes lipid metabolism and recovery, and atorvastatin (a PPARG agonist) reverses altered metabolic processes. Macrophages and microglia play complex roles in SCI. Targeting PPARG and its agonists is a promising therapeutic approach for SCI. Macrophages infiltrate the spinal cord post-injury, decreasing over time. Microglia phagocytose myelin debris, increasing lipid accumulation. Macrophage deletion improves outcomes, while microglial deletion worsens them. The LD+ microglia subtype shows abnormal Pparg signaling. PPARG promotes lipid metabolism and recovery, and atorvastatin reverses altered metabolic processes. Targeting PPARG and its agonists offers a promising therapeutic approach for spinal cord injury. Abstract Spinal cord injury (SCI) substantially affects functional capacity and the immune system plays a crucial role in recovery. Examining alterations in microglia metabolism can lead to improved repair mechanisms; however, the molecular subtyping of microglia lacks consensus. In this study, the effects of SCI on macrophages and microglia in mice are investigated to identify tailored therapeutic targets and interventions for patients with SCI. Macrophages infiltrate the spinal cord shortly after injury; however, infiltration decreases over time. Microglial phagocytosis of myelin debris is associated with increased lipid accumulation. Macrophage deletion improves outcomes, whereas microglial deletion worsens them. The PLIN2+ microglia subtype in lipid droplet formation shows abnormal activation of the Pparg signaling pathway compared with that with other subtypes. PPARG promotes lipid metabolism and recovery, and atorvastatin (a PPARG agonist) reverses altered metabolic processes. Macrophages and microglia play complex roles in SCI. Targeting PPARG and its agonists is a promising therapeutic approach for SCI. Advanced Science, Volume 12, Issue 43, November 20, 2025.