Liproxstatin-1 improves functional recovery after acute spinal cord injury by inhibiting ferroptosis-induced...

Ferroptosis, a regulated form of cell death mediated by iron-dependent lipid peroxidation, is implicated in the secondary phase of acute spinal cord injury (ASCI). However, its specific molecular network and interaction with inflammatory processes within the ASCI context remain elusive. We investigated the ferroptosis inhibitor Liproxstatin-1 in a rat T10 contusion model. Post-injury Liproxstatin-1 treatment was evaluated using behavioral assessments, histology, transcriptomics, and biochemical assays. ASCI triggered widespread transcriptomic changes, including altered expression of ferroptosis-related modules involved in lipid peroxidation, iron metabolism, and antioxidant defense. Liproxstatin-1 improved motor function and balance, reduced tissue cavitation, neuronal loss, and gliosis. Transcriptomic analysis indicated that Liproxstatin-1 modulated genes associated with inflammation, immune cell migration, and Toll-like receptor/NLRP3 signaling. In HT22 cells, Liproxstatin-1 counteracted Erastin-induced ferroptosis, reducing ROS, restoring glutathione, lowering lipid peroxidation, and downregulating HMGB1, TLR4, TNF-α, and NLRP3. In vivo, Liproxstatin-1 reduced iron deposition, restored glutathione, attenuated lipid peroxidation, reversed GPX4 downregulation, and suppressed inflammatory protein elevation. These findings indicate that Liproxstatin-1 confers neuroprotection in ASCI by concurrently inhibiting ferroptosis and associated inflammatory activation, thereby highlighting ferroptosis as a potential therapeutic target.