7,8-dihydroxyflavone exerts neuroprotective effects against traumatic brain injury in mice via the TrkB-dependent anti-ferroptotic ERK/CREB/GPX4 pathway.

Traumatic brain injury (TBI) triggers severe secondary brain damage with ferroptosis as a key driver. 7,8-dihydroxyflavone (7,8-DHF), a selective TrkB agonist, has known neuroprotective properties, yet its regulatory role in TBI-related ferroptosis remains unclear. This study aimed to explore whether 7,8-DHF alleviates TBI injury via modulating ferroptosis and its underlying molecular pathway. We established a mouse TBI model and an in vitro scratch injury model in HT22 cells. Behavioral tests, histological staining, biochemical detection and western blot were performed to assess neurological function, neuronal loss, neuroinflammation, ferroptosis markers and TrkB downstream signaling. In vivo results showed reduces iron deposition, lipid peroxidation and inflammatory cytokines to alleviate neuronal death and rescue motor and cognitive dysfunction, Cellular experiments further verified its anti-ferroptotic activity. Mechanistically, 7,8-DHF activated TrkB-dependent ERK/CREB signaling to upregulate glutathione peroxidase 4 (GPX4), clearing cytotoxic lipid peroxides to suppress ferroptosis. Inhibition of TrkB or CREB abolished the above protective effects. In summary, 7,8-DHF relieves TBI-induced neuronal damage, ferroptosis and neuroinflammation through the TrkB/ERK/CREB/GPX4 cascade, offering an alternative therapeutic strategy for TBI secondary injury.