Chloride Channel-3 promotes ferroptosis of traumatic brain injury via SGK1/GSK3β pathway.

Abstract

Traumatic brain injury (TBI) is a major cause of high mortality and long-term disability worldwide. The secondary injury mechanisms associated with TBI involve a range of complex processes, including excitotoxicity, mitochondrial dysfunction, oxidative stress, lipid peroxidation, neuroinflammation, and iron deposition. Ferroptosis, an iron-dependent form of regulated cell death, has recently been implicated in TBI pathogenesis. Here, we investigated the role of chloride channel-3 (CLC-3) in ferroptosis after TBI. Using clinical specimens, in vivo rat models, and in vitro cell assays, we found that CLC-3 expression was significantly upregulated following TBI, accompanied by increased ferroptosis. Mechanistically, CLC-3 promoted ferroptosis through activation of the SGK1/GSK3β signaling pathway. Importantly, knockdown of CLC-3 reduced ferroptosis, alleviated neuronal injury, and improved neurological outcomes. These findings identify CLC-3 as a critical regulator of ferroptosis in TBI and suggest it as a promising therapeutic target for clinical intervention.