Pyruvate alleviates traumatic brain injury by suppressing glutamate-driven ferroptosis via the xCT/GPX4 axis

Traumatic brain injury (TBI) triggers toxic glutamate release and ferroptosis, contributing to neuronal death. This study investigated whether sodium pyruvate confers neuroprotection by reducing central glutamate and inhibiting ferroptosis. Using a murine TBI model, we found that pyruvate treatment rapidly lowered serum glutamate levels by enhancing hepatic alanine aminotransferase (ALT) activity. Subsequently, cerebrospinal fluid (CSF) glutamate decreased, likely facilitated by a disrupted blood-brain barrier (BBB). Pyruvate restored the cystine/glutamate antiporter xCT (System Xc⁻)/ glutathione peroxidase 4 (GPX4) antioxidant axis, increased glutathione, reduced lipid peroxidation, iron deposition, and improved mitochondrial function, thereby attenuating ferroptosis. These effects were abolished by the xCT inhibitor Erastin. Furthermore, pyruvate treatment reduced neuronal loss, decreased lesion volume, and improved long-term neurological and cognitive function in behavioral tests. In conclusion, intravenous pyruvate protects against TBI by peripherally scavenging glutamate and centrally inhibiting ferroptosis via the xCT/GPX4 pathway.