NRF2 ameliorates TBI-triggered Parkinsonism: synchronized antioxidant defense and neuroinflammation suppression.

Traumatic brain injury (TBI) confers long-term vulnerability to progressive neurological sequelae, including Parkinsonian-like symptoms. Impaired redox homeostasis and neuroinflammation may drive neurodegeneration post-TBI, while the pathological mechanisms and targetable molecular checkpoints remain unidentified. In this study, we found individuals with a history of TBI exhibited dopaminergic neuronal damage in the substantia nigra (SN), accompanied by increased oxidative stress and gliosis. Through 6-month longitudinal analysis of murine SN post-TBI, we uncovered insufficient NRF2 expression in the late phase in SN after TBI. Genetic Nrf2 ablation exacerbated PD (Parkinson's disease) -like motor deficits and α-synuclein aggregation in dopaminergic neuron in SN through the disruption of oxidative stress, glial reactivity and neuroinflammation. Conversely, pharmacological NRF2 activation using dimethyl fumarate (DMF) over 1, 3 and 6 months ameliorated oxidative damage and glial reactivity, suppressed pro-inflammatory cascades, and preserved motor function of TBI mice. These findings provide compelling evidence that NRF2 insufficiency as the key molecular linchpin for TBI-induced Parkinsonian‑like pathology. By coordinating antioxidant, anti-inflammatory, and glia-modulatory effects, NRF2 may serve as a potential therapeutic target for TBI-associated Parkinsonism or Parkinsonian-like neurodegeneration.