Histone lactylation exacerbates neuronal ferroptosis after traumatic brain injury: The effect of the upregulation of TNFAIP3 by mediating mitochondrial damage through the deubiquitination of ENO1.

Alleviating various forms of programmed neuronal death resulting from mechanical injury has long driven the development of neurotherapeutic strategies for traumatic brain injury (TBI). This study aimed to elucidate the potential role of tumor necrosis factor alpha-induced protein 3 (TNFAIP3) in neuronal ferroptosis and to clarify the specific mechanisms through which it influences the prognosis of TBI. We observed differential expression of TNFAIP3 protein between TBI and sham-operated mice. Quantitative polymerase chain reaction (qPCR) and Western blot analyses revealed a significant upregulation of TNFAIP3 in neurons following brain injury. TNFAIP3 promoted stretch-induced neuronal ferroptosis and contributed to impaired motor and learning performance in mice after TBI. Mechanistically, TNFAIP3 stabilized Enolase 1 (ENO1) protein levels by mediating its deubiquitination. TNFAIP3-induced mitochondrial damage increased reactive oxygen species (ROS) production, ultimately exacerbating neuronal ferroptosis. Upregulation of TNFAIP3 in neurons was associated with enhanced histone lactylation following TBI. Lactic acid treatment further promoted neuronal ferroptosis by elevating TNFAIP3 expression. Collectively, our findings indicate that TNFAIP3 may serve as a potential therapeutic target for improving outcomes in patients with traumatic brain injury.