TNFAIP3 affects ferroptosis after traumatic brain injury by affecting the deubiquitination and ubiquitination pathways of the HMOX1 protein and ACSL3.

The occurrence and progression of traumatic brain injury involve a complex process. The pathophysiological mechanisms triggered by neuronal damage include various forms of programmed cell death, including ferroptosis. We observed upregulation of TNFAIP3 in mice after traumatic brain injury. Overexpression of TNFAIP3 inhibits HT-22 proliferation and cell viability through ferroptosis. Mechanistically, TNFAIP3 interacts with the HMOX1 protein and promotes its stability through the deubiquitination pathway. Additionally, TNFAIP3 can enhance lipoperoxidation, mitochondrial damage, and neuronal cell death by promoting ACSL3 degradation via NEDD4-mediated ubiquitination. Mice injected with AAV-shTNFAIP3 exhibited reduced neuronal degeneration and improved motor and cognitive function following cortical impact injury. In conclusion, our findings demonstrate that TNFAIP3 deficiency inhibits neuronal cell ferroptosis and ameliorates cognitive impairment caused by traumatic brain injury and demonstrate its potential applicability in the treatment of traumatic brain injury.