Fascin-1 Limits Secondary Damage by Preventing Oxidative‑Stress‑Induced Microglial Death After Spinal Cord Injury

Secondary injury after spinal cord injury (SCI) is driven by oxidative stress, microglial activation, and apoptosis. Fascin‑1, an actin‑bundling protein implicated in immune regulation, may influence these processes, but its role in SCI remains unclear. We analyzed a mouse spinal cord single‑nucleus RNA‑seq dataset across five time points after T9 SCI to define cell-type-specific Fascin‑1 dynamics. We modeled oxidative stress in human (HMC3) and mouse (BV2) microglia using H₂O₂ and assessed the effects of Fascin‑1 overexpression on viability, apoptosis, reactive oxygen species (ROS), redox biomarkers, and apoptosis/antioxidant proteins. In a rat contusion SCI model, we delivered AAV‑Fascin‑1 and evaluated locomotor recovery, histopathology, apoptosis, redox indices, and protein expression. Single‑nucleus analysis reveal that Fscn1 expression transiently decreased in microglia and astrocytes early after SCI, then recovered. In vitro, Fascin‑1 overexpression enhanced microglial viability under H₂O₂, reduced apoptosis and ROS, decreased MDA, restored SOD/GPx activity and the GSH/GSSG balance, downregulated Bax and cleaved Caspase‑3/9, and upregulated Bcl-2. In vivo, AAV‑Fascin‑1 improved BBB scores from day 7 to 14 post‑SCI, reduced lesion cavitation and fibrotic scarring, preserved Nissl‑positive neurons, and normalized redox indices and apoptosis/antioxidant protein levels. Fascin‑1 mitigates oxidative stress and apoptosis in microglia and attenuates secondary damage via activation of the NRF2/HO‑1 axis after SCI. These findings identify FSCN1 as a potential therapeutic target to enhance functional recovery following SCI.