Novel role of GADD45A in synergistic regulation of neuronal ferroptosis and apoptosis after spinal cord injury via NF-κB signaling.

Ferroptosis and apoptosis are major mechanisms of neuronal injury after spinal cord injury (SCI), but regulators that coordinate both processes remain poorly defined. In this study, we analyzed 188 ferroptosis-related differentially expressed genes (FRDEGs) at 7 day (7d) after SCI and identified GADD45A as a central gene in the post-SCI ferroptosis network, with a functional profile closely linked to apoptosis. GADD45A was markedly upregulated in injured spinal cord tissue. In vivo, GADD45A knockdown improved neurological recovery and promoted tissue repair by modulating markers of ferroptosis and apoptosis. In H2O2-treated PC12 cells, GADD45A knockdown reduced the expression of Cleaved Caspase-3, BAX, Cleaved Caspase-9, 4-HNE, and ACSL4, while increasing the expression of BCL-2, GPX4, FTH1, and FPN. It also attenuated H2O2-induced cellular injury. Mechanistically, GADD45A knockdown inhibited NF-κB signaling and reduced nuclear translocation of NF-κB-p65. These protective effects were reversed by the NF-κB activator CU-T12-9. Collectively, these findings suggest that GADD45A promotes neuronal ferroptosis and apoptosis after SCI by regulating the NF-κB pathway, and that GADD45A may be a potential therapeutic target for SCI.